Differential Modulation of Caveolin-1 Expression in Cells of the Vasculature by Statins

Plenz, Gabriele; Hofnagel, Oliver; Robenek, Horst

doi:10.1161/01.cir.0000111128.83347.7a

Cited by 41 publications

(30 citation statements)

References 6 publications

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“…Additional important effects of statin treatment on eNOS function include inhibition of caveolin (60,61). Statins also increase eNOS activity via posttranslational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3K/Akt) pathway (55).…”

Section: Statins and Endothelial Functionmentioning

confidence: 99%

Pleiotropic Effects of Statins

Liao

Laufs

2005

Annu. Rev. Pharmacol. Toxicol.

1,612

1,198

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Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.

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Section: Statins and Endothelial Functionmentioning

confidence: 99%

Pleiotropic Effects of Statins

Liao

Laufs

2005

Annu. Rev. Pharmacol. Toxicol.

1,612

1,198

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“…Second, statins reduce caveolin-1 abundance. Caveolin-1 is an integral membrane protein and binds to eNOS in caveolae, thereby inhibiting NO production directly [76]. Third, statins can activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway [77].…”

Section: Statins and Vascular Dysfunctionmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

538

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…Treatment with lovastatin stimulated caveolin-1 expression, whereas pravastatin showed no effect in SMCs. In macrophages, both statins increased caveolin-1 mRNA levels [113]. Therefore, the mechanism(s) underlying caveolin-1 modulation might be different depending on the cell type analyzed and/or the type of statin used (i.e., hydrophobic vs hypophilic) and may reflect also the observed pleiotropic effects of statins [114].…”

Section: Pharmacological Modulation Of Caveolin-1 In the Vasculaturementioning

confidence: 99%

Caveolae and Caveolin-1: Novel Potential Targets for the Treatment of Cardiovascular Disease

Frank¹,

Hassan²,

Rodríguez-Feo³

et al. 2007

CPD

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Caveolae are 50-100 nm cell surface plasma membrane invaginations that are highly enriched in cholesterol and sphingolipids and are characterized by the protein marker caveolin-1. Caveolin-1 is highly expressed in terminally differentiated cells. Among these cells, endothelial cells, smooth muscle cells, and macrophages have all been shown to play key roles in the development of vascular disease. Atherosclerosis and neointimal formation are two major processes that have been associated with arterial occlusion. In both cases, caveolin-1 has been shown to play an important role. However, depending on the cell type and the metabolic pathways regulated by this protein, caveolin-1 may positively or negatively influence the development of vascular disease. Both of these aspects will be discussed in this review.

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Differential Modulation of Caveolin-1 Expression in Cells of the Vasculature by Statins

Cited by 41 publications

References 6 publications

Pleiotropic Effects of Statins

Pleiotropic Effects of Statins

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Caveolae and Caveolin-1: Novel Potential Targets for the Treatment of Cardiovascular Disease

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