Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Derk, Chris T.; Jimenez, Sergio A.

doi:10.1016/j.autrev.2005.06.010

Cited by 32 publications

(18 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Along this line, interfering with myofibroblast-dependent vascular remodelling, it has been speculated that statins could have a beneficial effect on SSc vasculopathy (45). Although not confirmed in all patient cohorts (46), this idea is supported by the finding that endothelial dysfunction appears also to be a trigger for atherosclerosis in SSc (47).…”

Section: Perivascular Alterationssupporting

confidence: 68%

Mechanisms of vascular damage in systemic sclerosis

et al. 2009

View full text Add to dashboard Cite

Although being classified as autoimmune connective tissue disease, dominant components of the pathophysiology of systemic sclerosis (SSc) consists of mechanisms of vascular damage, which can occur early in the course of the disease. Amongst them are abnormal vasoreactivity, hypoxia, insufficient neoangiogenesis and direct damage of vascular and perivascular cells. They result in a decreased capillary blood flow, and subsequently in clinically overt symptoms such as Raynaud's syndrome and fingertip ulcers. In addition, in active disease vascular pathology can affect various other organs, predominantly the lung, the kidney, the heart but also the gastrointestinal tract. Vascular pathology contributes also significantly to overall morbidity and mortality in SSc patients and reduces life expectancy by at least a decade. Fortunately, molecular biology has revealed a number of underlying pathways on the cellular and subcellular levels, including key factors of the aberrant function of (peri)vascular cells and autoimmune effector cells, the dysregulation of vasoconstrictive molecules and their receptors, the upregulation of intracellular signaling kinases and the altered balance of hypoxia-induced vascular growth factors. This increasing knowledge of vascular pathology in SSc has also resulted in novel therapeutic approaches ranging from endothelin antagonists to application of progenitor cells to counteract this aberrant vascular pathology and to support the repair of the dysfunctional vasculature.

show abstract

Section: Perivascular Alterationssupporting

confidence: 68%

Mechanisms of vascular damage in systemic sclerosis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The results obtained indicate that statins are powerful inhibitors of type I collagen gene expression in normal and systemic sclerosis fibroblasts, and this is likely attributable to their effects on geranylgeranyl prenylation of key intracellular mediators. Previous results demonstrating the pleiotropic protective effects of these drugs on various endothelial and immune cell functions (19)(20)(21) coupled with the potent inhibitory effects of statins on type I collagen gene expression suggest that these drugs may be effective therapeutic agents in systemic sclerosis and other diseases that are characterized by tissue fibrosis and vascular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…This effect was initially believed to be solely related to the cholesterol-lowering effects of the statins. However, there is increasing evidence that these agents may exert profound endothelial and vascular protective effects beyond their lipid-lowering action (19)(20)(21). These later clinical and experimental observations have led to a wealth of research studies examining the pleiotropic effects of statins, including modification of vascular disease and certain immune responses (for review, see ref.…”

Section: Discussionmentioning

confidence: 99%

“…These later clinical and experimental observations have led to a wealth of research studies examining the pleiotropic effects of statins, including modification of vascular disease and certain immune responses (for review, see ref. 21). Indeed, statins have been shown to down-regulate the expression of TGF␤1 by renal mesangial cells in models of renal nephropathy in which fibrosis is mediated by TGF␤1 and connective tissue growth factor (CTGF), and to reduce CTGF mRNA levels in normal human and rodent mesangial cell lines, in human renal fibroblast cell lines, and in human lung fibroblasts from patients with idiopathic pulmonary fibrosis (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Louneva¹,

Huaman²,

Fertala³

et al. 2006

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.Methods. Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 M and 10 M of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl-coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding.Results. Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing ؊174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells.

show abstract

“…In the presence of ATV and inhibition of isopentenyl pyrophosphate production, the addition of exogenous FPP is not sufficient to generate GGPP for geranylgeranylation. 5,28,29 RhoA is one of those geranylgeranylated proteins, 5,30 but RhoB undergoes both geranylgeranylation and farnesylation. 31,32 Our results showing GGPP reversion of the ATV effect and its inhibition of RhoA membrane translocation and activation in human vascular SMCs, therefore, further suggest a role for RhoA in ATV-inhibited gene transcription of myocardin.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

Jiang²,

Yin³

et al. 2012

Hypertension

View full text Add to dashboard Cite

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...

show abstract

Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Cited by 32 publications

References 46 publications

Mechanisms of vascular damage in systemic sclerosis

Mechanisms of vascular damage in systemic sclerosis

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Atorvastatin Inhibits Myocardin Expression in Vascular Smooth Muscle Cells

Contact Info

Product

Resources

About