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Marta Ruizortega - One of the best experts on this subject based on the ideXlab platform.
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statins inhibit angiotensin ii smad pathway and related Vascular Fibrosis by a tgf β independent process
PLOS ONE, 2010Co-Authors: Raul Rodrigues Diez, Carolina Lavoz, Sandra Rayegomateos, Esther Civantos, Raquel Rodriguesdiez, Juan Rodriguezvita, Jesús Egido, Sergio Mezzano, Marta RuizortegaAbstract:We have recently described that in an experimental model of atherosclerosis and in Vascular smooth muscle cells (VSMCs) statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β), leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII) activates the Smad pathway and contributes to Vascular Fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced Vascular Fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-Fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours). All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced Vascular damage.
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hmg coa reductase inhibitors decrease angiotensin ii induced Vascular Fibrosis role of rhoa rock and mapk pathways
Hypertension, 2007Co-Authors: Monica Ruperez, Raquel Rodriguesdiez, Juan Rodriguezvita, Jesús Egido, Elsa Sanchezlopez, Vanesa Esteban, Gisselle Carvajal, Luis Miguel Blancocolio, Juan Jose Plaza, Marta RuizortegaAbstract:3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardioVascular diseases. Angiotensin II (Ang II) contributes to cardioVascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured Vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II–induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II–induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II–mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a Vascular Fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardioVascular diseases.
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tgf β signaling in Vascular Fibrosis
Cardiovascular Research, 2007Co-Authors: Marta Ruizortega, Juan Rodriguezvita, Elsa Sanchezlopez, Gisselle Carvajal, Jesús EgidoAbstract:Transforming growth factor-β (TGF-β) participates in the pathogenesis of multiple cardioVascular diseases, including hypertension, restenosis, atherosclerosis, cardiac hypertrophy and heart failure. TGF-β exerts pleiotropic effects on cardioVascular cells, regulating cell growth, Fibrosis and inflammation. TGF-β has long been believed to be the most important extracellular matrix regulator. We review the complex mechanisms involved in TGF-β-mediated Vascular Fibrosis that includes the Smad signaling pathway, activation of protein kinases and crosstalk between these pathways. TGF-β blockade diminishes Fibrosis in experimental models, however better antifibrotic targets are needed for an effective therapy in human fibrotic diseases. A good candidate is connective tissue growth factor (CTGF), a downstream mediator of TGF-β-induced Fibrosis. Among the different factors involved in Vascular Fibrosis, Angiotensin II (AngII) has special interest. AngII can activate the Smad pathway independent of TGF-β and shares with TGF-β many intracellular signals implicated in Fibrosis. Blockers of AngII have demonstrated beneficial effects on many cardioVascular diseases and are now one of the best options to block TGF-β fibrotic responses. A better knowledge of the intracellular signals of TGF-β can provide novel therapeutic approaches for fibrotic diseases.
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endothelin 1 via eta receptor and independently of transforming growth factor β increases the connective tissue growth factor in Vascular smooth muscle cells
Circulation Research, 2005Co-Authors: Juan Rodriguezvita, Marta Ruizortega, Elsa Sanchezlopez, Monica Ruperez, Juan Jose Plaza, Vanessa Esteban, Jesús EgidoAbstract:Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardioVascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In Vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in Vascular Fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1–treated cells, showing that CTGF participates in ET-1–induced ECM accumulation. The ET A , but not ET B , antagonist diminished ET-1–induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ET A receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-β– and angiotensin (Ang) II–induced Fibrosis. In VSMCs, ET-1 did not upregulate TGF-β gene or protein. The presence of neutralizing transforming growth factor (TGF)-β antibody did not modify ET-1–induced CTGF production, showing a TGF-β–independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ET A antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-β and through the activation of several intracellular signals via ET A receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in Vascular diseases.
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endothelin 1 via eta receptor and independently of transforming growth factor β increases the connective tissue growth factor in Vascular smooth muscle cells
Circulation Research, 2005Co-Authors: Juan Rodriguezvita, Marta Ruizortega, Elsa Sanchezlopez, Monica Ruperez, Juan Jose Plaza, Vanessa Esteban, Jesús EgidoAbstract:Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardioVascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In Vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in Vascular Fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-beta- and angiotensin (Ang) II-induced Fibrosis. In VSMCs, ET-1 did not upregulate TGF-beta gene or protein. The presence of neutralizing transforming growth factor (TGF)-beta antibody did not modify ET-1-induced CTGF production, showing a TGF-beta-independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-beta and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in Vascular diseases.
Jeanclaude Dussaule - One of the best experts on this subject based on the ideXlab platform.
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asymmetric dimethylarginine adma induces chronic kidney disease through a mechanism involving collagen and tgf β1 synthesis
The Journal of Pathology, 2011Co-Authors: Fabrice Mihout, Jeanclaude Dussaule, Nasim Shweke, Naike Bige, Chantal Jouanneau, Pierre RoncoAbstract:Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is accumulated in plasma during chronic kidney disease (CKD). It is considered an independent mortality and cardioVascular risk factor in CKD patients. To test the involvement of ADMA in CKD progression, we investigated the effects of chronic ADMA administration on renal structure and compared these effects with NG-nitro-L-arginine methyl ester (L-NAME) treatment, a widely used exogenous inhibitor of NOS that induces CKD. Three groups of uninephrectomized mice were studied: ADMA (60 mg/kg per day), L-NAME (60 mg/kg per day), and isotonic saline (control) were infused through osmotic mini-pumps for 8 weeks. ADMA and L-NAME induced hypertension (PAS 167 ± 16 and 168 ± 10 versus 100 ± 4 mmHg, p < 0.01, respectively). High level of ADMA was associated with increased renal oxidative stress. ADMA treatment induced glomerular and Vascular Fibrosis as evidenced by the elevated deposits of collagen I, III, and fibronectin (p < 0.01). A similar profile was observed in the L-NAME group. Mice treated with ADMA had reduced peritubular capillaries versus controls (p < 0.01). Collagen I mRNA expression and renal TGF-β1 concentrations were higher in the ADMA and L-NAME groups. Increased level of TGF-β1 was associated with a significant rise of HIF-1α and endothelin-1 expression. These results demonstrate for the first time that elevated concentrations of ADMA are associated with the development of renal Fibrosis. These data suggest that in pathophysiological conditions of endothelial dysfunction, the exaggerated endogenous synthesis of ADMA could contribute to CKD progression by favouring hypertension, extracellular matrix synthesis, and rarefaction of peritubular capillaries.
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epidermal growth factor receptor trans activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice
The FASEB Journal, 2003Co-Authors: Martin Flamant, Pierrelouis Tharaux, Sandrine Placier, Christos Chatziantoniou, Daniel Henrion, Thomas M Coffman, Jeanclaude DussauleAbstract:Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated Vascular Fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin-induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin-induced increase of blood pressure was blunted in the waved-2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the Vascular tissue: contractility and fibrogenesis.
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angiotensin ii activates collagen type i gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and tgf β
Journal of The American Society of Nephrology, 2001Co-Authors: Fadi Fakhouri, Sandrine Placier, Raymond Ardaillou, Jeanclaude Dussaule, Christos ChatziantoniouAbstract:Hypertension is frequently associated with the development of renal Vascular Fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta.
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angiotensin ii activates collagen i gene through a mechanism involving the map er kinase pathway
Hypertension, 2000Co-Authors: Pierrelouis Tharaux, Christos Chatziantoniou, Fadi Fakhouri, Jeanclaude DussauleAbstract:Abstract —Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal Vascular Fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-α 2 chain promoter [procolα 2 (I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolα 2 (I) activity in freshly isolated aortas and renal cortical slices ( P 2 (I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFκB (PDTC) did not have any effect in the Ang II–induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c- fos proto-oncogene. This increase of c- fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-β (TGF-β), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-β–induced activation of procolα 2 (I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-β signaling pathways.
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angiotensin ii activates collagen i gene through a mechanism involving the map er kinase pathway
Hypertension, 2000Co-Authors: Pierrelouis Tharaux, Christos Chatziantoniou, Fadi Fakhouri, Jeanclaude DussauleAbstract:Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal Vascular Fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
Christos Chatziantoniou - One of the best experts on this subject based on the ideXlab platform.
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epidermal growth factor receptor trans activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice
The FASEB Journal, 2003Co-Authors: Martin Flamant, Pierrelouis Tharaux, Sandrine Placier, Christos Chatziantoniou, Daniel Henrion, Thomas M Coffman, Jeanclaude DussauleAbstract:Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension-associated Vascular Fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen-activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin-induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin-induced increase of blood pressure was blunted in the waved-2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the Vascular tissue: contractility and fibrogenesis.
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angiotensin ii activates collagen type i gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and tgf β
Journal of The American Society of Nephrology, 2001Co-Authors: Fadi Fakhouri, Sandrine Placier, Raymond Ardaillou, Jeanclaude Dussaule, Christos ChatziantoniouAbstract:Hypertension is frequently associated with the development of renal Vascular Fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta.
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angiotensin ii activates collagen i gene through a mechanism involving the map er kinase pathway
Hypertension, 2000Co-Authors: Pierrelouis Tharaux, Christos Chatziantoniou, Fadi Fakhouri, Jeanclaude DussauleAbstract:Abstract —Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal Vascular Fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-α 2 chain promoter [procolα 2 (I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolα 2 (I) activity in freshly isolated aortas and renal cortical slices ( P 2 (I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFκB (PDTC) did not have any effect in the Ang II–induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c- fos proto-oncogene. This increase of c- fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-β (TGF-β), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-β–induced activation of procolα 2 (I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-β signaling pathways.
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angiotensin ii activates collagen i gene through a mechanism involving the map er kinase pathway
Hypertension, 2000Co-Authors: Pierrelouis Tharaux, Christos Chatziantoniou, Fadi Fakhouri, Jeanclaude DussauleAbstract:Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal Vascular Fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
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angiotensin ii activates collagen type i gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis evidence for an endothelin mediated mechanism
Circulation, 1999Co-Authors: Jeanjacques Boffa, Pierrelouis Tharaux, Sandrine Placier, Raymond Ardaillou, Jeanclaude Dussaule, Christos ChatziantoniouAbstract:weeks of L-NAME treatment (P,0.01) and at 14 weeks reached 3- and 8-fold increases over control in afferent arterioles and glomeruli, respectively ( P,0.001). Losartan, an AT1 receptor antagonist, given simultaneously with L-NAME prevented the increase of procola2(I) levels and attenuated the development of renal Vascular Fibrosis without normalizing systolic pressure increase. Because we found previously that endothelin mediated renal Vascular Fibrosis in the L-NAME model, the interaction between Ang II, endothelin, and procola2(I) was investigated in ex vivo and short-term in vivo experiments. In both conditions, the Ang II‐induced activation of procola2(I) in renal cortex was blocked by an endothelin receptor antagonist. Conclusions—During chronic inhibition of NO, the collagen I gene becomes activated, leading to the development of renal Vascular Fibrosis. Ang II is a major player in this fibrogenic process, and its effect on collagen I gene is independent of systemic hemodynamics and is at least partly mediated by the profibrogenic action of endothelin. (Circulation. 1999;100:1901-1908.)
Olga V Fedorova - One of the best experts on this subject based on the ideXlab platform.
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cardiotonic steroids induce Vascular Fibrosis via pressure independent mechanism in nacl loaded diabetic rats
Journal of Cardiovascular Pharmacology, 2019Co-Authors: Olga V Fedorova, Yulia Grigorova, Valentina Zernetkina, Edward G Lakatta, Artem V Fadeev, Courtney A Marshall, A O Konradi, Nikolai I Kolodkin, Natalia I Agalakova, Alexei Y BagrovAbstract:Endogenous cardiotonic steroid, marinobufagenin (MBG), induces Fli1-dependent tissue Fibrosis. We hypothesized that an increase in MBG initiates the development of aortic Fibrosis in salt-loaded rats with type 2 diabetes mellitus (DM2) via pressure-independent mechanism. DM2 was induced by a single intraperitoneal administration of 65 mg/kg streptozotocin to neonatal (4-5 days) male Wistar rats. Eight-week-old DM2 rats received water or 1.8% NaCl (DM-NaCl) solution for 4 weeks (n = 16); half of DM-NaCl rats were treated with anti-MBG monoclonal antibody (mAb) (DM-NaCl-AB) during week 4 of salt loading; control intact rats received water (n = 8/group). Blood pressure, MBG, erythrocyte Na/K-ATPase activity, aortic weights, levels of Fibrosis markers (Fli1, protein kinase Cδ, transforming growth factor-β1, receptors of the transforming growth factor beta5, fibronectin, collagen-1), and sensitivity of the aortic explants to the vasorelaxant effect of sodium nitroprusside were assessed. No changes in systolic blood pressure were observed while erythrocyte Na/K-ATPase was inhibited by 30%, plasma MBG was doubled, and aortic markers of Fibrosis became elevated in DM-NaCl rats versus control. Treatment of DM-NaCl rats with anti-MBG mAb activated Na/K-ATPase, prevented increases in aortic weights, and the levels of Fibrosis markers returned to the control levels. The responsiveness of the aortic rings from DM-NaCl rats to the relaxant effect of sodium nitroprusside was reduced (half maximal effective concentration (EC50) = 29 nmol/L) versus control rings (EC50 = 7 nmol/L) and was restored by anti-MBG mAb (EC50 = 9 nmol/L). Our results suggest that in salt-loaded diabetic rats, MBG stimulates aortic collagen synthesis in a pressure-independent fashion and that 2 profibrotic mechanisms, Fli1 dependent and transforming growth factor-β dependent, underlie its effects.
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aortic Fibrosis induced by high salt intake in the absence of hypertensive response is reduced by a monoclonal antibody to marinobufagenin
American Journal of Hypertension, 2016Co-Authors: Yulia Grigorova, Olga V Fedorova, Ondrej Juhasz, Valentina Zernetkina, Kenneth W Fishbein, Edward G Lakatta, Alexei Y BagrovAbstract:BACKGROUND Marinobufagenin (MBG) is an endogenous Na/K-ATPase inhibitor, a natriuretic and a vasoconstrictor. MBG is implicated in salt-sensitive hypertension, cardiac hypertrophy, and initiate the pro-fibrotic signaling. Previously it was demonstrated that immunoneutralization of an endogenous MBG by 3E9 anti-MBG-antibody (mAb) in vivo lowered blood pressure (BP) and reversed cardiac Fibrosis in salt-sensitive, and in partially nephrectomized rats. In the present study, we investigated whether mAb alleviates Vascular remodeling induced in normotensive rats on high salt intake. METHODS Wistar rats (5 months old) received normal (CTRL; n = 8) or high salt intake (2% NaCl in drinking water) for 4 weeks ( n = 16). Rats from the group on a high salt intake were administered vehicle (SALT; n = 8) or mAb (50 µg/kg) (SALT-AB; n = 8) during the last week of high salt diet. BP, erythrocyte Na/K-ATPase activity, levels of MBG in plasma and 24-hour urine, and sensitivity of aortic explants to the vasorelaxant effect of sodium nitroprusside (SNP) were measured. Aortic collagen abundance was determined immunohistochemically. RESULTS In SALT vs. CTRL, heightened levels of MBG were associated with inhibition of erythrocyte Na/K-ATPase in the absence of BP changes. High salt intake was accompanied by a 2.5-fold increase in aortic collagen abundance and by a reduction of sensitivity of aortic explants to the vasorelaxant effect of SNP following endothelin-1-induced constriction. In the SALT-AB group, all NaCl-mediated effects were reversed by immunoneutralization of MBG. CONCLUSIONS High salt intake in young normotensive rats can induce Vascular Fibrosis via pressure-independent/MBG-dependent mechanisms, and this remodeling is reduced by immunoneutralization of MBG.
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marinobufagenin induced Vascular Fibrosis is a likely target for mineralocorticoid antagonists
Journal of Hypertension, 2015Co-Authors: Olga V Fedorova, Yulia Grigorova, Ondrej Juhasz, Edward G Lakatta, Elena V Frolova, Igor V Emelianov, Konstantin A Bagrov, Wen Wei, Courtney A Marshall, A O KonradiAbstract:OBJECTIVE Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate Vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG. METHODS Experiment 1: Explants of thoracic aortae and aortic Vascular smooth muscle cells from Wistar rats were cultured for 24 h in the presence of vehicle or MBG (100 nmol/l) with or without canrenone (10 μmol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56 ± 2 years) with resistant hypertension on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity, plasma MBG, and erythrocyte Na/K-ATPase before and 6 months after addition of placebo (n = 8) or spironolactone (50 mg/day; n = 8) to the therapy. RESULTS In rat aortic explants and in Vascular smooth muscle cells, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC50 = 480 ± 67 vs. 23 ± 3 nmol/l in vehicle-treated rings; P < 0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of Vascular rings to sodium nitroprusside (EC50 = 17 ± 1 nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/l; P = 0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs. 2.8 ± 0.2 μmol Pi/ml per h, P < 0.01) vs. seven healthy individuals. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in pulse wave velocity and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels. CONCLUSION MBG-induced Vascular Fibrosis is a likely target for spironolactone.
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abstract 14650 a monoclonal antibody to a sodium pump inhibitor marinobufagenin reversed aortic remodeling and stiffness in normotensive rats on a high salt intake
Circulation, 2014Co-Authors: Yulia N Grigorova, Olga V Fedorova, Ondrej Juhasz, Valentina Zernetkina, Edward G Lakatta, Wen Wei, Alexei Y BagrovAbstract:Background: Marinobufagenin (MBG), an endogenous cardiotonic steroid, is a Na/K-ATPase inhibitor and a vasoconstrictor. Previously it was demonstrated, that administration of 3E9 anti-MBG-antibody (mAb) reduced blood pressure (BP) and reversed left ventricular Fibrosis in animal models of salt-sensitive hypertension and nephropathy. In the present study we investigated whether mAb alleviates BP and Vascular remodeling in normotensive rats on a high salt intake. Methods: Wistar rats (5 months old) received normal salt diet (CTRL; n=8) or high salt intake (2% NaCl in drinking water) for 4 weeks. Rats on a high salt were administered vehicle (SALT; n=8) or mAb (50 ug/kg) (SALT-AB; n=8) 3 times during the last week of a high salt diet. BP was measured at baseline, after 3 and 4 weeks of experiment. Na/K-ATPase activity was measured in erythrocytes. Aortas were weighed, and were used to study sensitivity to the vasorelaxant effect of sodium nitroprusside (SNP), and for the histochemistry analysis of collagen deposition. Renal 24-hr MBG excretion was measured at week 4. Results: In SALT vs. CTRL, in the absence of BP changes, elevated levels of MBG (14.1±1.1 vs. 9.0±1.6 pmol/24hr, p Conclusion: These findings for the first time demonstrated that in normotensive rats on a high salt intake heightened MBG levels induced Vascular Fibrosis and impairment of vasorelaxation in the absence of blood pressure changes. Immunoneutralization of MBG reversed these changes. Thus, high dietary NaCl intake in normotensive animals can stimulate Vascular Fibrosis via pressure-independent/ MBG-dependent mechanisms, and this remodeling is reversible.
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in preeclampsia endogenous cardiotonic steroids induce Vascular Fibrosis and impair relaxation of umbilical arteries
Journal of Hypertension, 2011Co-Authors: Elena R Nikitina, Natalia I. Tapilskaya, Anton V Mikhailov, Ekaterina S Nikandrova, Elena V Frolova, Artem V Fadeev, Vera V Shman, Victoria Shilova, Joseph I Shapiro, Olga V FedorovaAbstract:BACKGROUND Marinobufagenin (MBG), a bufadienolide cardiotonic steroid, induces cardioVascular Fibrosis. Because levels of MBG in preeclampsia are increased, and anti-MBG monoclonal antibody reduces blood pressure (BP) in a rat model of preeclampsia, we hypothesized that in preeclampsia, elevated MBG levels would be associated with the development of Fibrosis in feto-placental circulation and with impairment of Vascular relaxation. METHOD We studied 16 patients with preeclampsia (systolic BP=150±4 mmHg; 28±2 years, 37±1 weeks gestational age) and 14 gestational age-matched normal pregnant women (systolic BP=112±2 mmHg). RESULTS Preeclampsia was associated with a rise in plasma and placental levels of MBG. In preeclamptic umbilical arteries, the expression of Fli-1, a transcription factor and a negative regulator of Fibrosis, was significantly reduced (P<0.001), whereas procollagen-1 expression was increased (P<0.01). As compared to control vessels, isolated rings of umbilical arteries from patients with preeclampsia demonstrated unaltered responsiveness to endothelin-1 (EC50=2.2 and 3.2 nmol/l, respectively), but exhibited an impaired response to the relaxant effect of sodium nitroprusside (EC50=1.5 vs. 32.4 nmol/l, P<.001) following endothelin-1-induced constriction. Ex-vivo treatment of normal umbilical arteries explants with 1 and 10 nmol/l MBG for 24 h mimicked the effects of preeclampsia, specifically suppressed Fli-1 and increased collagen-1 expression while impairing vasorelaxation. CONCLUSION Our results indicate that in preeclampsia, elevated levels of MBG induce Vascular Fibrosis via a Fli-1-dependent mechanism which leads to an impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy of this syndrome.
Jesús Egido - One of the best experts on this subject based on the ideXlab platform.
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statins inhibit angiotensin ii smad pathway and related Vascular Fibrosis by a tgf β independent process
PLOS ONE, 2010Co-Authors: Raul Rodrigues Diez, Carolina Lavoz, Sandra Rayegomateos, Esther Civantos, Raquel Rodriguesdiez, Juan Rodriguezvita, Jesús Egido, Sergio Mezzano, Marta RuizortegaAbstract:We have recently described that in an experimental model of atherosclerosis and in Vascular smooth muscle cells (VSMCs) statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β), leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII) activates the Smad pathway and contributes to Vascular Fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced Vascular Fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-Fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours). All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced Vascular damage.
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hmg coa reductase inhibitors decrease angiotensin ii induced Vascular Fibrosis role of rhoa rock and mapk pathways
Hypertension, 2007Co-Authors: Monica Ruperez, Raquel Rodriguesdiez, Juan Rodriguezvita, Jesús Egido, Elsa Sanchezlopez, Vanesa Esteban, Gisselle Carvajal, Luis Miguel Blancocolio, Juan Jose Plaza, Marta RuizortegaAbstract:3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardioVascular diseases. Angiotensin II (Ang II) contributes to cardioVascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured Vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II–induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II–induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II–mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a Vascular Fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardioVascular diseases.
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tgf β signaling in Vascular Fibrosis
Cardiovascular Research, 2007Co-Authors: Marta Ruizortega, Juan Rodriguezvita, Elsa Sanchezlopez, Gisselle Carvajal, Jesús EgidoAbstract:Transforming growth factor-β (TGF-β) participates in the pathogenesis of multiple cardioVascular diseases, including hypertension, restenosis, atherosclerosis, cardiac hypertrophy and heart failure. TGF-β exerts pleiotropic effects on cardioVascular cells, regulating cell growth, Fibrosis and inflammation. TGF-β has long been believed to be the most important extracellular matrix regulator. We review the complex mechanisms involved in TGF-β-mediated Vascular Fibrosis that includes the Smad signaling pathway, activation of protein kinases and crosstalk between these pathways. TGF-β blockade diminishes Fibrosis in experimental models, however better antifibrotic targets are needed for an effective therapy in human fibrotic diseases. A good candidate is connective tissue growth factor (CTGF), a downstream mediator of TGF-β-induced Fibrosis. Among the different factors involved in Vascular Fibrosis, Angiotensin II (AngII) has special interest. AngII can activate the Smad pathway independent of TGF-β and shares with TGF-β many intracellular signals implicated in Fibrosis. Blockers of AngII have demonstrated beneficial effects on many cardioVascular diseases and are now one of the best options to block TGF-β fibrotic responses. A better knowledge of the intracellular signals of TGF-β can provide novel therapeutic approaches for fibrotic diseases.
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endothelin 1 via eta receptor and independently of transforming growth factor β increases the connective tissue growth factor in Vascular smooth muscle cells
Circulation Research, 2005Co-Authors: Juan Rodriguezvita, Marta Ruizortega, Elsa Sanchezlopez, Monica Ruperez, Juan Jose Plaza, Vanessa Esteban, Jesús EgidoAbstract:Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardioVascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In Vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in Vascular Fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1–treated cells, showing that CTGF participates in ET-1–induced ECM accumulation. The ET A , but not ET B , antagonist diminished ET-1–induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ET A receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-β– and angiotensin (Ang) II–induced Fibrosis. In VSMCs, ET-1 did not upregulate TGF-β gene or protein. The presence of neutralizing transforming growth factor (TGF)-β antibody did not modify ET-1–induced CTGF production, showing a TGF-β–independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ET A antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-β and through the activation of several intracellular signals via ET A receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in Vascular diseases.
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endothelin 1 via eta receptor and independently of transforming growth factor β increases the connective tissue growth factor in Vascular smooth muscle cells
Circulation Research, 2005Co-Authors: Juan Rodriguezvita, Marta Ruizortega, Elsa Sanchezlopez, Monica Ruperez, Juan Jose Plaza, Vanessa Esteban, Jesús EgidoAbstract:Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardioVascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In Vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in Vascular Fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-beta- and angiotensin (Ang) II-induced Fibrosis. In VSMCs, ET-1 did not upregulate TGF-beta gene or protein. The presence of neutralizing transforming growth factor (TGF)-beta antibody did not modify ET-1-induced CTGF production, showing a TGF-beta-independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-beta and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in Vascular diseases.
