Articles in PresS. Am J Physiol Heart Circ Physiol (January 16, 2009). doi:10.1152/ajpheart.01176.2008
1 Title: Angiotensin II, mitochondria, cytoskeletal and extracellular matrix connections: an integrating viewpoint.
Authors: Elena MV de Cavanagh (1), Marcelo Ferder (1), Felipe Inserra (1, 2), Leon Ferder (3)
Affiliations: (1) Institute of Cardiovascular Pathophysiology (INFICA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina; (2) Fresenius Medical Care Argentina, Buenos Aires, Argentina; (3) Physiology and Pharmacology Department, Ponce School of Medicine, Ponce, Puerto Rico.
Running head: Mitochondria, angiotensin and cardiovascular diseases.
Contact information: León Ferder, MD; Physiology and Pharmacology Department, Ponce School of Medicine, P.O. Box 7004, Ponce, Puerto Rico, 00732-7004 USA. TE/FAX: (787) 841-3736. Email:
[email protected]
Keywords: mitochondria, angiotensin, cytoskeleton, extracellular matrix, cardiovascular disease.
Copyright © 2009 by the American Physiological Society.
2 Abstract Malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage associated with hypertension, and other disease conditions. Eukaryotic cells move, assume their shape, resist mechanical stress, accommodate their internal constituents, and transmit signals by relying on the constant remodeling of cytoskeleton filaments. Mitochondrial ATP is needed to support cytoskeletal dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal motility, morphology, localization and function. Extracellular matrix (ECM) quantity and quality influences cellular growth, differentiation, morphology, survival, and mobility. Mitochondria can sense ECM composition changes, and changes in mitochondrial functioning modify the ECM. Maladaptive ECM and cytoskeletal alterations occur in a number of cardiac conditions and in most types of glomerulosclerosis, leading to cardiovascular and renal fibrosis, respectively. Angiotensin-II (Ang-II) -a vasoactive peptide and growth factor- stimulates cytosolic and mitochondrial oxidant production, eventually leading to mitochondrial dysfunction. Also, by inducing integrin/focal adhesion changes, Ang-II regulates ECM and cytoskeletal composition and organization and accordingly contributes to the pathogenesis of cardiovascular remodeling. Ang-II-initiated integrin signalling results in the release of TGF-β1, a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by Ang-II is preceded by Ang-II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. Ang-II-dependent TGF-β1 release is a potential link between Ang-II, ECM and cytoskeleton derangements and mitochondrial dysfunction. It is necessary to emphasize that the present hypothesis is among many other plausible explanations for Ang-II-mediated mitochondrial dysfunction. A potential limitation of this proposal is that the results compiled here were obtained in different cells, tissues and/or experimental models.
3 1. The multifunctional mitochondrion and disease In addition to energy production, mitochondria also conduct other key cellular tasks, including the regulation of cytosolic calcium levels (29) and tissue oxygen gradients (104), H2O2 signalling (11), and the modulation of apoptosis (12). Importantly, mitochondria also receive, integrate and transmit signals, thus playing a critical role in cellular responses to a variety of stimuli (38). In consequence, mitochondrial damage may lead to the impairment of various aspects of tissue functioning. Accumulating evidence supports the notion that malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage (43), associated with hypertension (26, 27, 107), cardiac failure, the metabolic syndrome and obesity (118), diabetes mellitus (23, 114), renal disease (44), atherosclerosis (96), as well as aging (25, 36, 46, 64).
2. Mitochondria and angiotensin II (Ang-II) Ang-II, a key component of the RAS, plays a pivotal role in the regulation of blood pressure, volume, and electrolyte balance. Derangements of the RAS contribute to hypertension and target-organ injury. Ang-II can induce oxidant stress by enhancing the generation of both NO (88) and NAD(P)H oxidase-derived superoxide (92), thereby promoting peroxynitrite formation. Ang-II can also induce eNOS uncoupling, i.e. switching from NO to superoxide production (74). In addition, Ang-II was found to stimulate mitochondrial reactive oxygen species (mtROS) production. In rat endothelial cells, Ang-II-induced mtROS generation activates redox-sensitive NF-kappaB, which is followed by stimulation of vascular cell adhesion molecule-1 expression, a cytokine involved in atherosclerosis lesion formation (89). In mice, acute (24 h) and chronic (14 day) Ang-II infusion led to decreased cardiac expression of mitochondrial electron transport chain and Krebs cycle genes (65), supporting previous observations that indicated a role for Ang-II in the depression of mitochondrial energy metabolism (16, 94, 99). Moreover, in rat vascular smooth muscle cells and aorta in vivo Ang-II lowers mitochondrial membrane potential as a result of stimulation of mtROS production (62). In cat myocardium, the response to stretch comprises the activation of NAD(P)H oxidase by Ang-II leading to mtROS release (13). Recently, it was shown
4 that the molecular mechanisms involved in Ang-II-mediated mitochondrial dysfunction (increased mitochondrial H2O2 production, and decreased mitochondrial glutathione, state 3 respiration, and membrane potential) include protein kinase C activation, which in turn activates bovine aortic endothelial cell NAD(P)H oxidase and stimulates peroxynitrite formation (28). Notably, mitochondrial dysfunction was associated with endothelial dysfunction as indicated by the decrease of endothelial NO production (28). Another link between Ang-II and mitochondrial dysfunction is suggested by data showing that mitochondrial p66Shc plays a crucial role in Ang-II-induced myocardial remodelling (42). p66Shc –a protein partially localized in the mitochondrial intermembrane space- was suggested to contribute to mitochondrial ROS production by substracting electrons from cytochrome c, and transferring them to oxygen to generate superoxide. Other evidence indicates a direct interaction between Ang-II and mitochondrial components. 125I-labeled Ang-II was detected in heart, brain and smooth muscle cell mitochondria and nuclei (91, 98). In rat adrenal zona glomerulosa, renin, angiotensinogen and ACE were detected within intramitochondrial dense bodies (85), and in rat cerebellar cortex mitochondria Ang-II immunoreactivity was also found (32). Therefore, it is apparent that the effects of Ang-II on mitochondria may be either a) dependent on NAD(P)H oxidase activation or b) direct. In this line, we have shown that in rodent models of hypertension, diabetes and aging, Ang-II blockade not only attenuates oxidant production, but also improves mitochondrial function (23, 25-27). In support of the proposed direct actions of AngII, recent data showed that in rat embryonic vascular smooth muscle cells Ang-II can exert effects from the cell interior, independently from extracellular actions, and seemingly through binding to intracellular receptors different from AT1 and AT2 receptors (35), or to AT1 nuclear receptors (69). Internalization of Ang-II can be mediated by internalization of AT1 receptors bound to Ang-II, as was reported in rat aortic smooth muscle cells (1), hepatocytes (54), human vascular smooth muscle cells (8) and renal proximal tubule epithelial cells (103) In some cells, Ang-II internalization is mediated by megalin, although this mechanism is thought to mark internalized Ang-II for decomposition (39).
5 2a. Mitochondria and angiotensin II inhibitors The renal and cardiac benefits of ACE inhibitors and Ang-II type I (AT1) receptor blockers in hypertension, cardiovascular disease and diabetes patients (10, 22, 86) seem to be -at least partly- independent from their blood pressure lowering actions (10, 22, 82, 84). In this regard, RAS inhibitors were proposed to act as a magic bullet against oxidant stress (79). To further investigate the cellular mechanisms responsible for the protective actions of RAS inhibitors, we set forth to study the effects of these drugs on mitochondria. First, we showed that ACE-inhibition (enalapril) in aging mice prevented the lowering of mitochondrial number (34), attenuated age-related mitochondrial structure changes in myocardiocytes and hepatocytes (unpublished observation), and significantly increased animal survival (34), suggesting that natural aging mechanisms had been altered in enalapril-treated animals. The latter action on mice survival is in agreement with recent data in rats (5). Later, we found that in aging rats long-term treatment with enalapril or AT1-receptor blocker (losartan) improved kidney mitochondria functioning, when compared with mitochondria isolated from untreated old rats (25). In the same study, a general improvement in mitochondrial number and structure was observed, indicating that both RAS inhibitor strategies protect mitochondrial components and function from certain effects of aging. In another study, we showed that in spontaneously hypertensive rats RAS inhibition -but not Ca2+ channel blockade (amlodipine)- protects kidney mitochondria from hypertension-related damage (26, 27). Furthermore, in streptozotocin-diabetic rats – a model of type-1 diabetes – losartan, but not amlodipine, protected kidney mitochondria function without normalizing plasma glucose (23). In accordance with our findings in the kidney, Ang-II inhibition was shown to improve cardiac mitochondria energy production (75, 76, 80), and in captopril-treated diabetic rats the expression of genes related to energy production was up-regulated (19). Concerning the potential factor(s) that may mediate the effects of Ang-II inhibitors on mitochondrial function, a recent study suggests that mitochondrial NO may contribute to the mitochondrial effects of enalapril in the kidney (87). Other studies showed that AT1-receptor blockers can modulate uncoupling protein (UCP) mRNA levels in mouse brown adipose tissue (3) and rat liver (21), or UCP protein content in rat kidney (25, 87). UCPs, by uncoupling mitochondrial electron transport from ATP production can affect mitochondrial energy output, as well as modulate mitochondrial oxidant production.
6 3.
The cytoskeleton, the extracellular matrix (ECM) and mitochondria
3a. The cytoskeleton influences mitochondrial morphology and function The ability of eukaryotic cells to move, assume their shape, resist mechanical stress, and accommodate their internal constituents –including organelles, proteins, RNA and other materials- depends on the proper functioning of the cytoskeleton. The three main types of cytoskeletal filaments, i.e. microtubules, microfilaments and intermediate filaments, form a dynamic structure whose constant remodeling is necessary for normal cytoskeletal function. Thus, cell survival depends on an equilibrium between the assembly and disassembly of tubulin, actin and other types of proteins, that compose microtubules, microfilaments, and intermediate filaments, respectively (53). The dynamic behavior of these filaments requires the input of energy, that is provided by hydrolysis of either GTP by tubulin or ATP by actin subunits. Less is known on the mechanism of assembly and disassembly of intermediate filaments, but protein phosphorylation/dephosphorylation seems to be involved. The functional efficacy of cytoskeletal microtubules, microfilaments and intermediate filaments is dependent on a number of accessory proteins that bind the filaments to each other and to other cell components. The accessory proteins include motor proteins that impel organelles or secretory vesicles along the filaments or move the filaments themselves by hydrolyzing ATP. Therefore, ATP-producing mitochondria are needed to support the energy requirements of cytoskeletal structure dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal organelle motility, morphology, localization and function (9). Thus, in multicellular eukaryotes mitochondria are transported along the microtubules, whereas in certain cells –such as neurons- actin filaments sustain short length mitochondrial displacements (37). Also, actin filaments mediate the immobilization of mitochondria at intracellular locations of intense neuronal ATP consumption (9), and the association of mitochondria with actin filaments seems to facilitate the recruitment of pro-apoptotic cytosolic proteins to initiate apoptosis (101). It is apparent that adequate distribution of mitochondria participates in sustaining organelle function and is necessary for cell survival (37).
7 The profoundly curved mitochondrial morphology is preserved –at least partly- by attachment of mitochondria to the cytoskeletal tubulin and actin filaments (113), and the interaction between mitochondria and vimentin, an intermediate filament protein, also contributes to maintain mitochondrial morphology and organization (102). Furthermore, experimental depression of actin turnover stimulates the release of reactive oxygen species (ROS) from yeast mitochondria, thereby promoting apoptosis (40). This behavior indicates that the inability to reorganize the actin cytoskeleton in response to external or internal signals leads to the impairment of cell function. In mammalian cells, circumstantial evidence also points to the involvement of altered actin dynamics in prompting apoptosis, which seems to be mediated by increased mitochondrial ROS production (40). Finally, because cytoskeletal filaments provide both a direct mechanical connection between most cell structures, and an extense negatively charged binding site for signaling molecules in response to activation of membrane receptors, the cytoskeleton participates in the transmission of signals from the plasma membrane to the cell interior (53). Considering the above mentioned functions, it is likely that disturbance of the cytoskeleton interferes with normal mitochondrial and cellular function and may lead to pathological consequences. Interestingly, abundant evidence shows that Ang-II induces cytoskeletal changes.
3a.i. Ang-II and the cytoskeleton In addition to its role as a vasoactive peptide, Ang-II is a growth factor that variously regulates the genetic expression of ECM proteins, other growth factors, cytokines, cell adhesion molecules and vasoactive agents, in vascular, cardiac, and kidney mesangial cells (59), and in this way can contribute to the pathogenesis of vascular remodeling in hypertension and atherosclerosis. Of note, Ang-II (93) induces changes in cytoskeletal filament organization (filament polymerization, stress fiber formation and assembly of focal adhesions) (for focal adhesions see 3c. The cytoskeleton-ECM connexion) (117), that also participate in pathologic vascular alteration. Thus, in rat vascular smooth muscle cells (VSMC) Ang-II stimulates the formation of actin stress fibers and focal adhesions as a result of c-Src activation (51), and induces polymerization and contraction of actin filaments as a result of p38 MAP kinase activation by a pathway that involved ROS generation, but not the classic AT1 receptor signaling
8 pathways (no activation of PKC or Tyr kinases) (72). In cultured rat VSMC, Ang II-stimulates tyrosine phosphorylation of paxillin and focal adhesion kinase –two components of actin-associated focal adhesions- via AT1 receptors (81), and these responses involve PKC-dependent and independent pathways and is accompanied by cytoskeletal reorganization (formation of actin stress fiber sand focal adhesions) (108) Conversely, disturbance of actin organization suppresses Ang-II mediated signaling (41). In addition, Ang-II prompts the phenotypic conversion of tubulointerstitial (115) and cardiac fibroblasts (14) into myofibroblasts, that express α-smooth muscle actin (α-SMA) which is not expressed in normal fibroblasts. Ang-II also stimulates the expression of α-SMA in glomerular mesangial cells (55), and human VSMC (2) and the intermediate filament protein desmin in glomerular epithelial cells (55). In agreement with the above data, chronic enalapril treatment prevented age- (49), and hyperoxaluria-related (106) α-SMA accumulation in rodent renal interstitium. Also, glomerular, and cortical and medullary interstitial α-SMA staining was significantly lower in quinapril-treated than in untreated obese Zucker rats (90). Summarizing, available evidence indicates that a) mitochondrial function is altered in response to both cytoskeletal disturbance and Ang-II, and b) Ang-II changes cytoskeletal organization. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by Ang-II is preceded by Ang-II-induced derangement of the cytoskeletal filament network.
3b. The ECM influences mitochondrial morphology and function The extracellular matrix (ECM) plays a key role in the maintenance of tissue structure and function. ECM turnover is largely regulated by firmly controlled matrix metalloproteases (MMP) activities. Abnormal turnover of matrix components is associated with disease (71). Although ECM remodeling is critical for proper development and tissue repair, faulty remodeling contributes to tissue fibrosis. Various high blood pressure conditions display cardiovascular and renal remodeling, which are manifested by tissue hypertrophy and inadequate changes in the quantity and quality of the ECM (17, 30), and lead to the pathogenesis of fibrotic diseases.
9 Accumulating evidence shows that mitochondria may act as sensors for changes in ECM composition. Thus, in genetically modified mice, skeletal muscle collagen VI deficiency resulted in structural mitochondria alterations –abnormal cristae and modified matrix density- and mitochondrial dysfunction, leading to muscle cell apoptosis (50). Fibronectin, another ECM protein, conveys survival signals for many cell types, protecting them from apoptosis (56). Accordingly, knockdown of fibronectin mRNA expression induced apoptosis in rat mesangial cells, and mitochondria-derived signaling was involved in the response (119). Also, under oxidative stress conditions, MMP-2 negatively regulates cardiac mitochondria function (122). Conversely, alteration of mitochondrial functioning triggers ECM changes. Thus, oxidative phosphorylation deficiency activates the transcription of ECM remodeling genes (including MMP) in cultured osteosarcoma cells (110). This evidence indicates that a delicate relationship seems to exist between the ECM and mitochondria. As described above for its ability to modify cytoskeletal organization, Ang-II also alters the protein composition of the ECM.
3.b.i. Ang-II and the ECM As already mentioned in Section 3.a.i. (Ang-II and the cytoskeleton) Ang-II is involved in the regulation of ECM protein gene expression. In the heart, ECM proteins are mainly produced by fibroblasts; therefore fibroblasts play a crucial role in cardiac fibrosis development. In cultured rat cardiac fibroblasts Ang-II increases the synthesis and secretion of collagen (18), fibronectin and laminin (52), and osteopontin expression (4). When infused into rats, Ang II induces the increase of left ventricular fibronectin, collagens I and III mRNAs (61). Rat vascular smooth muscle cells exposed to Ang-II display increased levels of collagen protein (57), fibronectin (100), laminin and tenascin (97) mRNA and protein. In vivo, infusion of Ang-II increases fibronectin mRNA and protein in rat aorta (60). Ang-II also stimulates the synthesis of ECM collagens, fibronectin and laminin by renal mesangial cells, tubular cells and interstitial fibroblasts. Seemingly, these effects are mediated by TGF-β and plasminogen activator inhibitor type 1 (PAI-1), among other factors (73).
10 Pharmacological inhibition of the RAS attenuates ECM deposition in the kidney and in the vasculature (for review see (59). In accordance with Ang-II actions on ECM production, chronic enalapril treatment reduced age-associated renal (49) and myocardial (48) collagen deposition in female mice, hyperoxaluria-related TGF-β and collagen type III immunostaining in the tubulointerstitial area (106), cavernous tissue collagen type III immunolabeling in spontaneously hypertensive rats (105), and collagen accumulation in the heart, liver and kidneys of streptozotocin-diabetic rats (24). At this point a new element can be added to the hypothesis proposed in Section 3.a.i., as follows. A body of evidence indicates that a) mitochondrial function is altered in response to cytoskeletal disturbance, ECM disturbance and Ang-II, and b) Ang-II changes both cytoskeletal and ECM organization. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by Ang-II is preceded by AngII-induced derangement of the cytoskeletal filament network and/or ECM organization.
3c. The cytoskeleton-ECM connexion. The cytoskeleton and the ECM are structurally and functionally connected through the integrins. Integrins are plasma membrane cell adhesion proteins that act as matrix receptors, and bind ECM proteins –including collagen, fibronectin, vitronectin and laminin- to the actin cytoskeleton. Importantly, binding of integrins to their ligands activates intracellular signaling pathways that provide the cells with critical information concerning the nature of the surroundings (7), allowing them to respond to the environment. Integrins not only sense the biochemical composition but also the mechanical properties of the ECM. Integrin-mediated cell adhesion signaling conveys information that influences the growth, division, differentiation, morphology, survival, programmed death, and mobility properties of the cell (66). Integrin receptors cluster at clearly defined ranges of cell contact with the ECM known as focal adhesions. Focal adhesions are large macromolecular assemblies involved in cell anchorage, that also function as biochemical signalling hubs by concentrating and directing signalling proteins. One of the earliest events in response to integrin stimulation is protein phosphorylation that results from activation of protein-tyrosine kinases, such as members of the Src-family and the cytoplasmic focal adhesion protein-tyrosine kinase (FAK) (95). Other intracellular second message systems
11 that are activated upon binding of integrins to their ligands include mitogen-activated protein (MAP) kinases, Rho family GTP-binding proteins, calcium channels, phosphatidylinositol- 4,5-bisphosphate, phospholipase-C, the Na/H antiporter, tyrosine and serine/threonine kinases, phosphatases, and cyclin D1. Integrins also transduce messages from the inside-out, whereby the intracellular milieu is able to regulate the adhesive activity of integrins. Of note, integrin-mediated signaling was recently found to modify mitochondrial function, leading to changes in gene expression and without triggering apoptosis (116). In this context, Ang-II was shown exert intracellular effects by inducing integrin/focal adhesion changes.
3.c.i Ang-II and integrins Abundant evidence indicates that the effects of Ang II on ECM formation involve changes in integrin/focal adhesion signalling. In rat cardiac fibroblasts, Ang-II -by acting on its AT1 receptor- enhances alpha(v), beta(1), beta(3), and beta(5) integrins, osteopontin, and alpha-actinin mRNA and protein levels, and this effect is accompanied with enhanced cell attachment to the ECM and phosphorylation of focal adhesion kinase (58). In cultured rat VSMC, Ang II stimulates paxillin and focal adhesion kinase phosphorylation via AT1 receptors (81). In adrenal glomerulosa cells, Ang II seems to inhibit proliferation and initiation of steroidogenesis by interfering with extracellular matrix/integrin signalling, at the level of paxillin binding to focal adhesions, which activates RhoA/B and Rac and disrupts actin stress fiber organization. (83). In human umbilical vein endothelial cells, Ang II stimulates integrin beta(3) expression in part by activating NF-kappaB (67). Importantly, studies in vivo using genetically altered mice lacking alpha(1)-integrin showed that signalling through alpha(1)beta(1)integrin and focal adhesions is involved in Ang-II-induced vascular hypertrophy (70).
3.c.ii. Ang-II, TGF-β, the ECM, the cytoskeleton and mitochondria In addition to the varied effects mentioned in Section 3a.i., Ang-II plays a pivotal role in fibrosis -at least in part- by stimulating transforming growth factor-β1 (TGF-β1) production and enhancing TGF-β1 signaling in
12 activated human hepatic stellate cells and rat cardiac fibroblasts (120), human lung fibroblasts (109), human kidney tubular epithelial cells (15), and human myocardium (63). TGF-β1 is a pleiotropic cytokine that plays a crucial role in the regulation of ECM assembly and remodeling, mainly by stimulating both the expression of collagens, fibronectin and proteoglycans, and the production of proteases that inhibit ECM breakdown. Persistent activation of TGF-β receptors leads to the anomalous connective tissue deposition associated to fibrotic disease (112). In mouse VSMC, the induction of TGF-β1 and collagen type I release by Ang II is dependent on alpha(v)beta(3)-integrin signalling (6). In rat cardiac fibroblasts, Ang II-induced expression of fibronectin and TGF-β is mediated by transactivation and downstream signalling of the epidermal growth factor receptor, and TGF-β contributes to the modulation of fibronectin mRNA stabilization (77). In the human myocardium, Ang-II seems to increase collagen expression indirectly by first increasing TGF-β1 expression (63). Appart from inducing ECM changes, binding of TGF-β to plasma membrane receptors activates intracellular signaling pathways that are involved in the regulation of actin cytoskeleton reorganization (111) (78). These actin filament rearrangements contribute to TGF-β effects on cell growth and differentiation (31). Interestingly, TGF-β seems to interact with mitochondria. Recently, TGF-β1 was found to induce growth arrest and acquisition of senescent phenotypes in lung epithelial cells, and this effect was mediated by decreased mitochondrial complex IV activity and the subsequent increase of mitochondrial ROS production (121). Treatment of fetal hepatocytes with TGF-β1 was followed by increased mitochondrial ROS generation, lowering of mitochondrial membrane potential and finally apoptosis (47). Also, TGF-β1 was found within mitochondria in rat and mouse cardiac myocytes and rat hepatocytes (45), and in mouse T lymphocytes (20) where it seems to contribute to maintain mitochondrial structure and function. These findings point to TGF-β1 as a potential link between Ang-II, ECM and cytoskeleton derangements, and mitochondrial dysfunction. Interestingly, Ang-II was recently shown to stimulate nuclear AT1a receptors directly to induce TGF-β1 transcription in rat renal cortical nuclei (68).
13 Summary and hypothesis Based on the above evidence the hypothesis proposed in Section 3.b.i. can be completed as follows. A body of evidence indicates that a) mitochondrial function is altered in response to cytoskeletal disturbance, ECM disturbance and Ang-II, b) by acting on its AT1 receptors, Ang-II changes both cytoskeletal and ECM organization, c) Ang-II exerts cytoskeletal and ECM effects by inducing integrin/focal adhesion changes, d) Ang-II-initiated integrin signalling results in the release of TGF-β1, a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by Ang-II is preceded by Ang-II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. Ang-II-dependent TGF-β1 release is a potential link between Ang-II, ECM and cytoskeleton derangements and mitochondrial dysfunction. It is necessary to emphasize that the present hypothesis is among many other plausible explanations for Ang-II-mediated mitochondrial dysfunction, since Ang-II has complex immediate effects. Thus, binding of Ang-II to its AT1 receptor not only activates various G-proteins and the Jak2/STAT pathway, but also transactivates platelet derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, and by homo- or heterodimerizing with AT1, AT2, bradykinin B2, β2-adrenergic, and dopamine D1 receptors activates other signaling pathways (33). Also, as mentioned in Section 2. (Mitochondria and angiotensin II) Ang-II stimulates cellular ROS production, which can have a crucial effect on mitochondria. A potential limitation of this proposal is that the results compiled in the present report were obtained in different tissues or cellular systems, by using various experimental models (See Tables 1 and 2) Further research is needed to confirm the veracity of the present proposal, which if proven to be correct would underscore the relevance of inhibiting the RAS to preserve mitochondrial structure and function in those conditions associated to the enhancement of Ang-II signalling.
14 Legend for Figure 1. Schematic representation of AT1 receptor-derived responses that are proposed to mediate Ang-II-dependent mitochondrial derangement. After binding to its AT1 receptor, Ang-II activates integrin-mediated signalling, thereby inducing alterations of both extracellular matrix (ECM) quality and quantity, and cytoskeletal protein composition and filament organization. These ECM/cytoskeletal changes can interfere not only with the mechanical properties of the extracellular and intracellular milieu leading to tissue malfunction, but also with mitochondrial distribution, structure and function. Therefore, in addition to potential direct oxidant-mediated effects of Ang-II on mitochondria, by modifying the cytoskeleton and ECM Ang-II indirectly contributes to the impairment of mitochondrial function, which in turn worsens cytoskeletal and ECM deterioration (vicious cycle). TGF-β1 is a potential link between Ang-II, ECM and cytoskeleton derangements, and mitochondrial dysfunction. = AT1-derived signaling;
= deleterious effect(s)
15 Table 1. Effects of Ang-II on mitochondria, the cytoskeleton and extracellular matrix
Tissue/Cell type
Experimental model
Reference
Rat aortic EC Bovine aortic EC Rat VSMC Rat aorta Cat myocardium
Cell culture Cell culture and isolated mitochondria Cell culture In vivo Ang-II infusion Response to stretch
(89) (28) (62) (62)
Rodent heart Rat VSMC
AngII in vivo infusion, mice Mouse heart failure model Rat heart failure model Cell culture
(65) (16, 94, 99) (16, 94, 99) (62)
Actin stress fiber and focal adhesion formation
Rat aortic VSMC
Cell culture
(51), (108)
Polymerization and contraction of actin filaments
Rat aortic VSMC
Cell culture
(72)
Tubulointerstitial fibroblasts Cardiac fibroblasts Glomerular mesangial cells Human VSMC
Cell culture In vivo Ang-II infusion In vivo Ang-II infusion Cell culture
(115) (14) (55) (2)
Glomerular epithelial cells
In vivo Ang-II infusion
(55)
Rat cardiac fibroblasts Rat left ventricle Rat VSMC Rat aorta Renal mesangial and tubular cells, and interstitial fibroblasts
Cell culture In vivo Ang-II infusion Cell culture In vivo Ang-II infusion
(18) (52) (4) (61) (57) (97, 100) (60)
Various experimental models
(73)
Effect Mitochondrial changes ↑ mtROS
↓ mt respiratory function
(13)
Cytoskeletal changes
Formation of α-SMA
Formation intermediate filament protein desmin
Extracellular matrix changes ↑ synthesis and/or secretion ECM proteins
Changes in integrin expression or signaling ↑ integrin expression
Changes in integrin signaling
Rat cardiac fibroblasts Human umbilical vein EC Mouse aorta
Rat VSMC Adrenal glomerulosa cells Mouse aorta
Cell culture Cell culture Ang-II administration to genetically altered mice Cell culture Cell culture Ang-II administration to genetically altered mice
EC= endothelial cells; VSMC= vascular smooth muscle cells; α-SMA = α-smooth muscle actin
(58) (67) (70) (81) (83) (70)
16 Table 2. Effects of Ang-II on TGF-β1 formation, and associated cytoskeletal and extracellular matrix changes
Effect
Tissue/Cell type
Experimental model
Reference
Human hepatic stellate cells and rat cardiac fibroblasts
Cell culture
(120)
Human lung fibroblasts Human kidney tubulo epithelial cells Human myocardium, cardiac fibroblasts
Cell culture Cell culture Biopsy incubation, cell culture
(109) (63)
↑ TGF-β1 depends on integrin signalling
Mouse VSMC
Cell culture
(6)
↑ TGF-β1 and fibronectin
Rat cardiac fibroblasts
Cell culture
(77)
↑ TGF-β1 and collagen
Human myocardium
Biopsy incubation
(63)
↑ TGF-β1 production & signaling
VSMC= vascular smooth muscle cells
(15)
17 References: 1. Anderson KM, Murahashi T, Dostal DE, and Peach MJ. Morphological and biochemical analysis of angiotensin II internalization in cultured rat aortic smooth muscle cells. Am J Physiol 264: C179-188, 1993. 2. Andrawis NS, Ruley EH, and Abernethy DR. Angiotensin II regulates human vascular smooth muscle alpha-actin gene expression. Biochem Biophys Res Commun 196: 962-968, 1993. 3. Araki K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, and Yoshimatsu H. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertension 48: 51-57, 2006. 4. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, and Hsueh WA. Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 98: 2218-2227, 1996. 5. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, and Inserra F. Protective effect of longterm angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293: H1351-1358, 2007. 6. Belmadani S, Zerfaoui M, Boulares HA, Palen DI, and Matrougui K. Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, alphavbeta3-integrin, and TGF-beta1 in response to ANG II and high glucose. Am J Physiol Heart Circ Physiol 295: H69-76, 2008. 7. Bershadsky AD, Balaban NQ, and Geiger B. Adhesion-dependent cell mechanosensitivity. Annu Rev Cell Dev Biol 19: 677-695, 2003. 8. Bkaily G, Sleiman S, Stephan J, Asselin C, Choufani S, Kamal M, Jacques D, Gobeil F, Jr., and D'Orleans-Juste P. Angiotensin II AT1 receptor internalization, translocation and de novo synthesis modulate cytosolic and nuclear calcium in human vascular smooth muscle cells. Can J Physiol Pharmacol 81: 274-287, 2003. 9. Boldogh IR and Pon LA. Interactions of mitochondria with the actin cytoskeleton. Biochim Biophys Acta 1763: 450-462, 2006. 10. Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, and Yusuf S. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation 112: 1339-1346, 2005. 11. Brookes PS, Levonen AL, Shiva S, Sarti P, and Darley-Usmar VM. Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species. Free Radic Biol Med 33: 755-764, 2002. 12. Brookes PS, Salinas EP, Darley-Usmar K, Eiserich JP, Freeman BA, Darley-Usmar VM, and Anderson PG. Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release. J Biol Chem 275: 20474-20479, 2000. 13. Caldiz CI, Garciarena CD, Dulce RA, Novaretto LP, Yeves AM, Ennis IL, Cingolani HE, Chiappe de Cingolani G, and Perez NG. Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium. J Physiol 584: 895-905, 2007. 14. Campbell SE, Janicki JS, and Weber KT. Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. J Mol Cell Cardiol 27: 1545-1560, 1995. 15. Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, Sanchez-Lopez E, Ruperez M, Cartier C, Esteban V, Ortiz A, Egido J, Mezzano SA, and Ruiz-Ortega M. Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation. Kidney Int 74: 585-595, 2008. 16. Casademont J and Miro O. Electron transport chain defects in heart failure. Heart Fail Rev 7: 131-139, 2002. 17. Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 80: 15L25L, 1997.
18 18. Crabos M, Roth M, Hahn AW, and Erne P. Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts. Coupling to signaling systems and gene expression. J Clin Invest 93: 2372-2378, 1994. 19. Chen G, Lin LX, Zhuang WT, Yao J, Huang HB, Liang JX, Zhang FL, Wen JP, Li LT, Lin M, and Lin QM. [Effects of captopril on myocardial tissue energy metabolism and inflammation in rats with diabetic cardiomyopathy]. Di Yi Jun Yi Da Xue Xue Bao 24: 827-828, 831, 2004. 20. Chen W, Jin W, Tian H, Sicurello P, Frank M, Orenstein JM, and Wahl SM. Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med 194: 439-453, 2001. 21. Chen YH, Yuan L, Chen YY, and Qi CJ. [The effects of renin-angiotensin system blockade on the liver steatosis in rats on long-term high-fat diet]. Zhonghua Nei Ke Za Zhi 47: 197-201, 2008. 22. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, and Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359: 995-1003, 2002. 23. de Cavanagh EM, Ferder L, Toblli JE, Piotrkowski B, Stella I, Fraga CG, and Inserra F. Renal mitochondrial impairment is attenuated by AT1 blockade in experimental Type I diabetes. Am J Physiol Heart Circ Physiol 294: H456-465, 2008. 24. de Cavanagh EM, Inserra F, Toblli J, Stella I, Fraga CG, and Ferder L. Enalapril attenuates oxidative stress in diabetic rats. Hypertension 38: 1130-1136, 2001. 25. de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, and Fraga CG. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. Faseb J 17: 1096-1098, 2003. 26. De Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Fraga CG, and Inserra F. Angiotensin II blockade improves mitochondrial function in spontaneously hypertensive rats. Cell Mol Biol (Noisy-le-grand) 51: 573-578, 2005. 27. de Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, and Inserra F. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol 290: R1616-1625, 2006. 28. Doughan AK, Harrison DG, and Dikalov SI. Molecular mechanisms of angiotensin IImediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102: 488-496, 2008. 29. Duszynski J, Koziel R, Brutkowski W, Szczepanowska J, and Zablocki K. The regulatory role of mitochondria in capacitative calcium entry. Biochim Biophys Acta 1757: 380-387, 2006. 30. Eberhardt W and Pfeilschifter J. Nitric oxide and vascular remodeling: spotlight on the kidney. Kidney Int Suppl: S9-S16, 2007. 31. Edlund S, Landstrom M, Heldin CH, and Aspenstrom P. Transforming growth factor-betainduced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13: 902-914, 2002. 32. Erdmann B, Fuxe K, and Ganten D. Subcellular localization of angiotensin II immunoreactivity in the rat cerebellar cortex. Hypertension 28: 818-824, 1996. 33. Feng YH, Ding Y, Ren S, Zhou L, Xu C, and Karnik SS. Unconventional homologous internalization of the angiotensin II type-1 receptor induced by G-protein-independent signals. Hypertension 46: 419-425, 2005. 34. Ferder L, Inserra F, Romano L, Ercole L, and Pszenny V. Effects of angiotensin-converting enzyme inhibition on mitochondrial number in the aging mouse. Am J Physiol 265: C15-18, 1993. 35. Filipeanu CM, Brailoiu E, Henning RH, Deelman LE, de Zeeuw D, and Nelemans SA. Intracellular angiotensin II inhibits heterologous receptor stimulated Ca2+ entry. Life Sci 70: 171-180, 2001. 36. Finkel T and Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 408: 239-247, 2000.
19 37. Frederick RL and Shaw JM. Moving mitochondria: establishing distribution of an essential organelle. Traffic 8: 1668-1675, 2007. 38. Goldenthal MJ and Marin-Garcia J. Mitochondrial signaling pathways: a receiver/integrator organelle. Mol Cell Biochem 262: 1-16, 2004. 39. Gonzalez-Villalobos R, Klassen RB, Allen PL, Navar LG, and Hammond TG. Megalin binds and internalizes angiotensin II. Am J Physiol Renal Physiol 288: F420-427, 2005. 40. Gourlay CW and Ayscough KR. A role for actin in aging and apoptosis. Biochem Soc Trans 33: 1260-1264, 2005. 41. Govindarajan G, Eble DM, Lucchesi PA, and Samarel AM. Focal adhesion kinase is involved in angiotensin II-mediated protein synthesis in cultured vascular smooth muscle cells. Circ Res 87: 710-716, 2000. 42. Graiani G, Lagrasta C, Migliaccio E, Spillmann F, Meloni M, Madeddu P, Quaini F, Padura IM, Lanfrancone L, Pelicci P, and Emanueli C. Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage. Hypertension 46: 433-440, 2005. 43. Gutierrez J, Ballinger SW, Darley-Usmar VM, and Landar A. Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res 99: 924-932, 2006. 44. Hall AM and Unwin RJ. The not so 'mighty chondrion': emergence of renal diseases due to mitochondrial dysfunction. Nephron Physiol 105: p1-10, 2007. 45. Heine UI, Burmester JK, Flanders KC, Danielpour D, Munoz EF, Roberts AB, and Sporn MB. Localization of transforming growth factor-beta 1 in mitochondria of murine heart and liver. Cell Regul 2: 467-477, 1991. 46. Hekimi S and Guarente L. Genetics and the specificity of the aging process. Science 299: 1351-1354, 2003. 47. Herrera B, Alvarez AM, Sanchez A, Fernandez M, Roncero C, Benito M, and Fabregat I. Reactive oxygen species (ROS) mediates the mitochondrial-dependent apoptosis induced by transforming growth factor (beta) in fetal hepatocytes. Faseb J 15: 741-751, 2001. 48. Inserra F, Romano L, Ercole L, de Cavanagh EM, and Ferder L. Cardiovascular changes by long-term inhibition of the renin-angiotensin system in aging. Hypertension 25: 437-442, 1995. 49. Inserra F, Romano LA, de Cavanagh EM, Ercole L, Ferder LF, and Gomez RA. Renal interstitial sclerosis in aging: effects of enalapril and nifedipine. J Am Soc Nephrol 7: 676-680, 1996. 50. Irwin WA, Bergamin N, Sabatelli P, Reggiani C, Megighian A, Merlini L, Braghetta P, Columbaro M, Volpin D, Bressan GM, Bernardi P, and Bonaldo P. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35: 367-371, 2003. 51. Ishida T, Ishida M, Suero J, Takahashi M, and Berk BC. Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require cSrc. J Clin Invest 103: 789-797, 1999. 52. Iwami K, Ashizawa N, Do YS, Graf K, and Hsueh WA. Comparison of ANG II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts. Am J Physiol 270: H21002107, 1996. 53. Janmey PA. The cytoskeleton and cell signaling: component localization and mechanical coupling. Physiol Rev 78: 763-781, 1998. 54. Jimenez E, Caro MC, Marsigliante S, and Montiel M. Angiotensin II receptor internalization and signaling in isolated rat hepatocytes. Biochem Pharmacol 57: 1125-1131, 1999. 55. Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J, and Schwartz SM. Renal injury from angiotensin II-mediated hypertension. Hypertension 19: 464-474, 1992. 56. Kapila YL, Wang S, and Johnson PW. Mutations in the heparin binding domain of fibronectin in cooperation with the V region induce decreases in pp125(FAK) levels plus proteoglycan-mediated apoptosis via caspases. J Biol Chem 274: 30906-30913, 1999. 57. Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, and Saruta T. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens 9: 17-22, 1991.
20 58. Kawano H, Cody RJ, Graf K, Goetze S, Kawano Y, Schnee J, Law RE, and Hsueh WA. Angiotensin II enhances integrin and alpha-actinin expression in adult rat cardiac fibroblasts. Hypertension 35: 273-279, 2000. 59. Kim S and Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52: 11-34, 2000. 60. Kim S, Ohta K, Hamaguchi A, Omura T, Tominaga K, Yukimura T, Miura K, Tanaka M, and Iwao H. AT1 receptor-mediated stimulation by angiotensin II of rat aortic fibronectin gene expression in vivo. Br J Pharmacol 113: 662-663, 1994. 61. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, and Iwao H. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 25: 1252-1259, 1995. 62. Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, and Abe Y. Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 45: 438-444, 2005. 63. Kupfahl C, Pink D, Friedrich K, Zurbrugg HR, Neuss M, Warnecke C, Fielitz J, Graf K, Fleck E, and Regitz-Zagrosek V. Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 46: 463-475, 2000. 64. Kwong LK and Sohal RS. Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse. Arch Biochem Biophys 373: 16-22, 2000. 65. Larkin JE, Frank BC, Gaspard RM, Duka I, Gavras H, and Quackenbush J. Cardiac transcriptional response to acute and chronic angiotensin II treatments. Physiol Genomics 18: 152166, 2004. 66. Larsen M, Artym VV, Green JA, and Yamada KM. The matrix reorganized: extracellular matrix remodeling and integrin signaling. Curr Opin Cell Biol 18: 463-471, 2006. 67. Li S, Wang X, Qiu J, Si Q, Wang H, Guo H, Sun R, and Wu Q. Angiotensin II stimulates endothelial integrin beta3 expression via nuclear factor-kappaB activation. Exp Aging Res 32: 47-60, 2006. 68. Li XC and Zhuo JL. Intracellular ANG II directly induces in vitro transcription of TGF-beta1, MCP-1, and NHE-3 mRNAs in isolated rat renal cortical nuclei via activation of nuclear AT1a receptors. Am J Physiol Cell Physiol 294: C1034-1045, 2008. 69. Licea H, Walters MR, and Navar LG. Renal nuclear angiotensin II receptors in normal and hypertensive rats. Acta Physiol Hung 89: 427-438, 2002. 70. Louis H, Kakou A, Regnault V, Labat C, Bressenot A, Gao-Li J, Gardner H, Thornton SN, Challande P, Li Z, and Lacolley P. Role of alpha1beta1-integrin in arterial stiffness and angiotensininduced arterial wall hypertrophy in mice. Am J Physiol Heart Circ Physiol 293: H2597-2604, 2007. 71. Mancini A and Di Battista JA. Transcriptional regulation of matrix metalloprotease gene expression in health and disease. Front Biosci 11: 423-446, 2006. 72. Meloche S, Landry J, Huot J, Houle F, Marceau F, and Giasson E. p38 MAP kinase pathway regulates angiotensin II-induced contraction of rat vascular smooth muscle. Am J Physiol Heart Circ Physiol 279: H741-751, 2000. 73. Mezzano SA, Ruiz-Ortega M, and Egido J. Angiotensin II and renal fibrosis. Hypertension 38: 635-638, 2001. 74. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, and Munzel T. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58-65, 2002. 75. Monteiro P, Duarte AI, Goncalves LM, and Providencia LA. Valsartan improves mitochondrial function in hearts submitted to acute ischemia. Eur J Pharmacol 518: 158-164, 2005. 76. Monteiro P, Gala S, Nobre S, Carreira R, Goncalves LM, and Providencia LA. Impact of imidapril on cardiac mitochondrial function in an ex-vivo animal model of global myocardial ischemia. Rev Port Cardiol 24: 53-61, 2005.
21 77. Moriguchi Y, Matsubara H, Mori Y, Murasawa S, Masaki H, Maruyama K, Tsutsumi Y, Shibasaki Y, Tanaka Y, Nakajima T, Oda K, and Iwasaka T. Angiotensin II-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circ Res 84: 1073-1084, 1999. 78. Moustakas A and Heldin CH. Dynamic control of TGF-beta signaling and its links to the cytoskeleton. FEBS Lett 582: 2051-2065, 2008. 79. Munzel T and Keaney JF, Jr. Are ACE inhibitors a "magic bullet" against oxidative stress? Circulation 104: 1571-1574, 2001. 80. Ochiai K, Hu Q, Lee J, Mansoor A, Liu J, Wang X, Gong G, Murakami Y, Ishibashi Y, Shimada T, and Zhang J. Functional and bioenergetic consequences of AT1 antagonist olmesartan medoxomil in hearts with postinfarction LV remodeling. J Cardiovasc Pharmacol 47: 686-694, 2006. 81. Okuda M, Kawahara Y, Nakayama I, Hoshijima M, and Yokoyama M. Angiotensin II transduces its signal to focal adhesions via angiotensin II type 1 receptors in vascular smooth muscle cells. FEBS Lett 368: 343-347, 1995. 82. Opie LH. Renoprotection by angiotensin-receptor blockers and ACE inhibitors in hypertension. Lancet 358: 1829-1831, 2001. 83. Otis M, Campbell S, Payet MD, and Gallo-Payet N. In adrenal glomerulosa cells, angiotensin II inhibits proliferation by interfering with fibronectin-integrin signaling. Endocrinology 149: 3435-3445, 2008. 84. Park JB, Intengan HD, and Schiffrin EL. Reduction of resistance artery stiffness by treatment with the AT(1)-receptor antagonist losartan in essential hypertension. J Renin Angiotensin Aldosterone Syst 1: 40-45, 2000. 85. Peters J, Kranzlin B, Schaeffer S, Zimmer J, Resch S, Bachmann S, Gretz N, and Hackenthal E. Presence of renin within intramitochondrial dense bodies of the rat adrenal cortex. Am J Physiol 271: E439-450, 1996. 86. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Jr., Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, and et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 327: 669-677, 1992. 87. Piotrkowski B, Fraga CG, and de Cavanagh EM. Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney. Am J Physiol Regul Integr Comp Physiol 292: R1494-1501, 2007. 88. Pueyo ME, Arnal JF, Rami J, and Michel JB. Angiotensin II stimulates the production of NO and peroxynitrite in endothelial cells. Am J Physiol 274: C214-220, 1998. 89. Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, and Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 20: 645-651, 2000. 90. Richards RJ, Porter JR, Inserra F, Ferder LF, Stella I, Reisin E, and Svec F. Effects of dehydroepiandrosterone and quinapril on nephropathy in obese Zucker rats. Kidney Int 59: 37-43, 2001. 91. Robertson AL, Jr. and Khairallah PA. Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle. Science 172: 1138-1139, 1971. 92. Rueckschloss U, Quinn MT, Holtz J, and Morawietz H. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 22: 1845-1851, 2002. 93. Sah VP, Seasholtz TM, Sagi SA, and Brown JH. The role of Rho in G protein-coupled receptor signal transduction. Annu Rev Pharmacol Toxicol 40: 459-489, 2000. 94. Sanbe A, Tanonaka K, Kobayasi R, and Takeo S. Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol 27: 2209-2222, 1995.
22 95. Schlaepfer DD and Hunter T. Signal transduction from the extracellular matrix--a role for the focal adhesion protein-tyrosine kinase FAK. Cell Struct Funct 21: 445-450, 1996. 96. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest 116: 1813-1822, 2006. 97. Sharifi BG, LaFleur DW, Pirola CJ, Forrester JS, and Fagin JA. Angiotensin II regulates tenascin gene expression in vascular smooth muscle cells. J Biol Chem 267: 23910-23915, 1992. 98. Sirett NE, McLean AS, Bray JJ, and Hubbard JI. Distribution of angiotensin II receptors in rat brain. Brain Res 122: 299-312, 1977. 99. Sorescu D and Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 8: 132-140, 2002. 100. Tamura K, Nyui N, Tamura N, Fujita T, Kihara M, Toya Y, Takasaki I, Takagi N, Ishii M, Oda K, Horiuchi M, and Umemura S. Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. J Biol Chem 273: 26487-26496, 1998. 101. Tang HL, Le AH, and Lung HL. The increase in mitochondrial association with actin precedes Bax translocation in apoptosis. Biochem J 396: 1-5, 2006. 102. Tang HL, Lung HL, Wu KC, Le AH, Tang HM, and Fung MC. Vimentin supports mitochondrial morphology and organization. Biochem J 410: 141-146, 2008. 103. Thekkumkara T and Linas SL. Role of internalization in AT(1A) receptor function in proximal tubule epithelium. Am J Physiol Renal Physiol 282: F623-629, 2002. 104. Thomas DD, Liu X, Kantrow SP, and Lancaster JR, Jr. The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2. Proc Natl Acad Sci U S A 98: 355-360, 2001. 105. Toblli J, Stella I, Nestor Mazza O, Ferder L, and Inserra F. Protection of cavernous tissue in male spontaneously hypertensive rats. Beyond blood pressure control. Am J Hypertens 17: 516-522, 2004. 106. Toblli JE, Stella I, de Cavanagh E, Angerosa M, Inserra F, and Ferder L. Enalapril prevents tubulointerstitial lesions by hyperoxaluria. Hypertension 33: 225-231, 1999. 107. Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension 44: 248-252, 2004. 108. Turner CE, Pietras KM, Taylor DS, and Molloy CJ. Angiotensin II stimulation of rapid paxillin tyrosine phosphorylation correlates with the formation of focal adhesions in rat aortic smooth muscle cells. J Cell Sci 108 ( Pt 1): 333-342, 1995. 109. Uhal BD, Kim JK, Li X, and Molina-Molina M. Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages. Curr Pharm Des 13: 1247-1256, 2007. 110. van Waveren C, Sun Y, Cheung HS, and Moraes CT. Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion. Carcinogenesis 27: 409-418, 2006. 111. Vardouli L, Vasilaki E, Papadimitriou E, Kardassis D, and Stournaras C. A novel mechanism of TGFbeta-induced actin reorganization mediated by Smad proteins and Rho GTPases. FEBS J 275: 4074-4087, 2008. 112. Verrecchia F and Mauviel A. Transforming growth factor-beta and fibrosis. World J Gastroenterol 13: 3056-3062, 2007. 113. Voeltz GK and Prinz WA. Sheets, ribbons and tubules - how organelles get their shape. Nat Rev Mol Cell Biol 8: 258-264, 2007. 114. Wallace DC. Mitochondrial diseases in man and mouse. Science 283: 1482-1488, 1999. 115. Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol 17: 467-491, 1997. 116. Werner E and Werb Z. Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J Cell Biol 158: 357-368, 2002. 117. Wesselman JP and De Mey JG. Angiotensin and cytoskeletal proteins: role in vascular remodeling. Curr Hypertens Rep 4: 63-70, 2002.
23 118. Wisloff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share Q, Fernstrom M, Rezaei K, Lee SJ, Koch LG, and Britton SL. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307: 418-420, 2005. 119. Wu D, Chen X, Guo D, Hong Q, Fu B, Ding R, Yu L, Hou K, Feng Z, Zhang X, and Wang J. Knockdown of fibronectin induces mitochondria-dependent apoptosis in rat mesangial cells. J Am Soc Nephrol 16: 646-657, 2005. 120. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199-210, 2008. 121. Yoon YS, Lee JH, Hwang SC, Choi KS, and Yoon G. TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells. Oncogene 24: 1895-1903, 2005. 122. Zhou HZ, Ma X, Gray MO, Zhu BQ, Nguyen AP, Baker AJ, Simonis U, Cecchini G, Lovett DH, and Karliner JS. Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction. Biochem Biophys Res Commun 358: 189-195, 2007.
Mitochondria Direct mitochondrial effect
)H (P se D NA xida o
AT1R
Indirect mitochondrial effect
TGF-β?
Foc adh
↑AngII al
esio n
Inte g
r in
α β
Cytoskeleton
↑Extracellular Matrix
