HMG-CoA Reductase Inhibitors Decrease Angiotensin II–Induced Vascular Fibrosis

Rupérez, Mónica; Rodrigues‐Díez, Raquel; Blanco-Colio, Luís Miguel; Sánchez-López, Elsa; Rodríguez-Vita, Juan; Esteban, Vanesa; Carvajal, Gisselle; Plaza, Juan José González; Egido, Jesús; Ruíz-Ortega, Marta

doi:10.1161/hypertensionaha.107.091264

Cited by 94 publications

(105 citation statements)

References 44 publications

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“…Ang II induces collagen deposition in different vascular beds. 23,24,27,34,35 Collagen might be located in the intracellular gaps between SMCs, thus explaining the increase in wall thickness. Accordingly, we observed greater collagen content in the media layer of MRA from Ang II-infused rats.…”

Section: Discussionmentioning

confidence: 99%

“…16,17,20 -22 We have demonstrated recently that statins inhibit several intracellular signaling systems activated by Ang II (RhoA/ Rho kinase and mitogen activated protein kinase [MAPK] pathways) involved in the regulation of profibrotic factors, eg, connective tissue growth factor, and in vascular fibrosis. 23 The aim of the present study was to evaluate whether statin treatment modulates the effects of Ang II on vascular remodeling, ECM deposition, and mechanical properties of resistance arteries and the possible role of oxidative stress in this modulation.…”

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confidence: 99%

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Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

et al. 2009

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Abstract-Angiotensin II (Ang II) modulates vasomotor tone, cell growth, and extracellular matrix deposition. This study analyzed the effect of atorvastatin in the possible alterations induced by Ang II on structure and mechanics of mesenteric resistance arteries and the signaling mechanisms involved. Wistar rats were infused with Ang II (100 ng/kg per day, SC minipumps, 2 weeks) with or without atorvastatin (5 mg/kg per day). Ang II increased blood pressure and plasmatic malondialdehyde levels. Compared with controls, mesenteric resistance arteries from Ang II-treated rats showed the following: (1) decreased lumen diameter; (2) increased wall/lumen; (3) decreased number of adventitial, smooth muscle, and endothelial cells; (4) increased stiffness; (5) increased collagen deposition; and (6) diminished fenestrae area and number in the internal elastic lamina. Atorvastatin did not alter blood pressure but reversed all of the structural and mechanical alterations of mesenteric arteries, including collagen and elastin alterations. In mesenteric resistance arteries, Ang II increased vascular O 2 ⅐Ϫ production and diminished endothelial NO synthase and CuZn/superoxide dismutase but did not modify extracellular-superoxide dismutase expression. Atorvastatin improved plasmatic and vascular oxidative stress, normalized endothelial NO synthase and CuZn/superoxide dismutase expression, and increased extracellularsuperoxide dismutase expression, showing antioxidant properties. Atorvastatin also diminished extracellular signalregulated kinase 1/2 activation caused by Ang II in these vessels, indicating an interaction with Ang II-induced intracellular responses. In vascular smooth muscle cells, collagen type I release mediated by Ang II was reduced by different antioxidants and statins. Moreover, atorvastatin downregulated the Ang II-induced NADPH oxidase subunit, Nox1, expression. Our results suggest that statins might exert beneficial effects on hypertension-induced vascular remodeling by improving vascular structure, extracellular matrix alterations, and vascular stiffness. These effects might be mediated by their antioxidant properties.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

et al. 2009

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“…Induction of CTGF by EGTA was dependent on signaling pathways which have earlier been described to regulate CTGF expression in epithelial cells, e.g. ERK and RhoA [19][20][21][22]. Inhibition of ERK1/2 by U0126 (0.5 M) abrogated CTGF induction.…”

Section: Egta-induced Ctgf Expression Is Related To Erk Activation Anmentioning

confidence: 74%

“…CTGF expression is regulated via RhoA/Rho kinase signaling [19,20,[23][24][25]. This pathway also played a role in the EGTA-mediated induction of CTGF which was sensitive to treatment with the inhibitor of Rho kinases, H1152 (Fig.…”

Section: Egta-induced Ctgf Expression Is Related To Erk Activation Anmentioning

confidence: 95%

Structural reorganization of the cytoskeleton contributes to the induction of pro-fibrotic connective tissue growth factor in tubular epithelial cells

Cicha

Goppelt‐Struebe

2016

JCB

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Abstract. BACKGROUND:Tissue injuries and pathological changes are often associated with changes in cell adhesion and reorganization of cytoskeletal structures. This is of particular relevance for renal epithelial cells, which form a highly regulated barrier along the nephron. Here, we investigated the effect of the calcium chelator EGTA on morphological alterations and changes in pro-fibrotic gene expression in proximal renal tubular epithelial cells. METHODS: Epithelial cells were exposed to EGTA alone or in combination with TGF␤-1, followed by the analysis of N-cadherin and paxillin localization and cytoskeletal rearrangement. The expression of connective tissue growth factor (CTGF), a pro-fibrotic protein regulated by alterations of cell morphology, was investigated. RESULTS: Even low concentrations of EGTA, which did not lead to the loss of cell-cell interactions or cell detachment, were sufficient to reduce N-cadherin binding, to rearrange focal adhesion, to induce CTGF expression, and to strongly enhance TGF␤-1-mediated signaling. These data indicate a substantial crosstalk between the changes in cell cytoskeletal structures at the cell-cell adhesions and the signaling of soluble mediators. CONCLUSIONS: By linking cell-cell and cell-matrix interactions with the regulation of pro-fibrotic signaling, our studies provide deeper insights into the physiological mechanisms underlying the natural regeneration and repair processes in the kidney.

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“…For example, in cultured vascular SMCs, pretreatment with ATV inhibited an angiotensin II-induced increase in GTP-bound RhoA, RhoA translocation from the cytosol to the membrane, and subsequent activation of the RhoA-ROCK pathway. 33 In addition, ATV treatment reduced the levels of activated RhoA in rat aorta in experimental models of hypertension induced by angiotensin II infusion. 33,34 Finally, a previous report showing that expression of SM-specific genes downstream of the RhoA-ROCK cascade, such as myocardin, desmin, SM ␣-actin, and SM22, was inhibited by ATV treatment in human fetal penile SMCs 16 provides further support to our conclusions.…”

Section: Discussionmentioning

confidence: 98%

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

Jiang²,

Yin³

et al. 2012

Hypertension

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Abstract-Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, is widely prescribed as a lipid-lowering drug. It also inhibits the RhoA-Rho-associated kinase pathway in vascular smooth muscle (SM) cells and critically inhibits SM function. Myocardin is a coactivator of serum response factor, which upregulates SM contractile proteins. The RhoA-Rho-associated kinase pathway, which directly triggers SM contraction, also increases myocardin gene expression. Therefore, we investigated whether ATV inhibits myocardin gene expression in SM cells. In mice injected with ATV (IP 20 g/g per day) for 5 days, myocardin gene expression was significantly downregulated in aortic and carotid arterial tissues with decreased expression of myocardin target genes SM ␣-actin and SM22. Correspondingly, the contractility of aortic rings in mice treated with ATV or the Rho-associated kinase inhibitor Y-27632 was reduced in response to treatment with either KCl or phenylephrine. In cultured mouse and human aortic SM cells, KCl treatment stimulated the expression of myocardin, SM ␣-actin, and SM22. These stimulatory effects were prevented by ATV treatment. ATV-induced inhibition of myocardin expression was prevented by pretreatment with either mevalonate or geranylgeranylpyrophosphate but not farnesylpyrophosphate. Treatment with Y-27632 mimicked ATV effects on the gene expression of myocardin, SM ␣-actin, and SM22, further suggesting a role for the RhoA-Rho-associated kinase pathway in ATV effects. Furthermore, ATV treatment inhibited RhoA membrane translocation and activation; these effects were prevented by pretreatment with mevalonate. We conclude that ATV inhibits myocardin gene expression in vivo and in vitro, suggesting a novel mechanism for ATV inhibition of vascular contraction. Statins inhibit production of isoprenoid intermediates in the cholesterol biosynthetic pathway, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), to reduce posttranslational modifications of several intracellular signaling proteins, including nuclear lamins, Ras, Rho, Rac, and Rap. 1-3 The Ras and Rho GTPase family members are the major substrates for posttranslational modification by prenylation. 4 These small GTP-binding proteins cycle between the inactive GDP-bound state and active GTP-bound state and play critical roles in the regulation of the actin cytoskeleton and intracellular signaling pathways. It has been shown that statins regulate subcellular location 1 and activation of Ras and Rho. 5 The inhibitory effect of statins on prenylation of these small G proteins, for example, RhoA, and, therefore, the RhoA-Rho-associated kinase (ROCK) pathway, is known to contribute to protection of the cardiovascular system beyond their cholesterol-lowering effects. 6 It is well known that the ROCK pathway stimulates contraction through inhibition of myosin light-chain phosphatase or phosphorylation of myosin light chain 20. 7,8 Statins attenuate spontaneous smooth muscle (SM) tone through inhibition of the...

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HMG-CoA Reductase Inhibitors Decrease Angiotensin II–Induced Vascular Fibrosis

Cited by 94 publications

References 44 publications

Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

Structural reorganization of the cytoskeleton contributes to the induction of pro-fibrotic connective tissue growth factor in tubular epithelial cells

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

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