Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase

Corsini, Alberto; Mazzotti, Matteo; Raiteri, M.; Soma, Maurizio R.; Gabbiani, Giulio; Fumagalli, R.; Paoletti, Rodolfo

doi:10.1016/0021-9150(93)90107-6

Cited by 209 publications

(111 citation statements)

References 40 publications

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“…Beyond the effect of reducing serum cholesterol, statins have other beneficial effects such as reduced expression of adhesion molecules, inhibition of the proliferation and migration of vascular smooth muscle cell [8,9], anti-thrombotic effects [10], and reduction of inflammation [11], which have been known as their pleiotropic effects. All statins commonly share such effects.…”

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confidence: 99%

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

et al. 2007

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Abstract. While a large numbers of clinical trials using various kinds of statins has been reported, a possible preventive effect on new onset of type 2 diabetes mellitus was shown only by the subanalysis of The West of Scotland Coronary Prevention Study (WOSCOPS) using pravastatin. The aim of this study was to investigate whether pravastatin has a preferable effect on glucose tolerance among statins. An open-label prospective cross-over trial was performed to compare the effect of pravastatin (10 mg/day) or atorvastatin (10 mg/day) in Japanese early-state type 2 diabetes mellitus with hypercholesterolemia. The analyzed study subjects were treated with pravastatin (10 mg/day, n = 12) or atorvastatin (10 mg/day, n = 12) for 12 weeks. After a 4-week-washout period, the drugs were switched and treatment was continued for another 12 weeks. Oral glucose tolerance test (OGTT) was performed to evaluate several parameters including the appropriateness of beta cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter and sensitivity) at the end of each therapy. HbA 1c and 2 h-glucose levels during OGTT in the pravastatin treatment were significantly lower than atorvastatin treatment. Disposition index after pravastatin treatment was significantly higher than after atorvastatin treatment. In conclusion, our study suggests that pravastatin has a favorable effect on pancreatic beta cell function compared with atorvastatin.

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Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

et al. 2007

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“…In addition to their hypocholesterolemic effect, statins are also known to possess pleiotropic effect such as reducing the expression of various adhesion molecules, inhibition of the proliferation and migration of vascular smooth muscle cells [5,6], anti-thrombotic effects [7], and suppression of inflammation [8]. The mechanism of the pleiotropic effect of statins seems to be mainly exerted by the reduction of intermediates of the mevalonate pathway.…”

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Acute Onset and Worsening of Diabetes Concurrent with Administration of Statins

et al. 2005

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Abstract. We report a patient in whom the administration of HMG CoA reductase inhibitors (statins) might have triggered the onset and worsening of diabetes. The patient was a 48-year-old Japanese man who underwent annual medical examination but had never been told of hyperglycemia. Four months after the commencement of atorvastatin (10 mg/day) treatment, a diagnosis of diabetes mellitus was made from his typical symptoms of hyperglycemia, postprandial plasma glucose level of 29.8 mmol/l and HbA 1c of 11.5%. After 2 months of insulin therapy and 3 months after the cessation of atorvastatin, almost complete resolution of diabetes was observed. During the subsequent 3 months, diet therapy alone was sufficient to control blood glucose level. Then, we prescribed pravastatin (20 mg/day). During the subsequent 3 months, HbA 1c was gradually increased. However, after discontinuation of pravastatin, HbA 1c was gradually decreased. In the general population, statin does not seem to have critical adverse effects on glucose tolerance, but it may uncommonly modify the natural course of the development of diabetes in certain patients.

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“…For example, treatment with HMG-CoA reductase inhibitors reduces post-angioplasty re-stenosis, coronary bypass occlusions (6,7), and transplant arteriosclerosis (8). Although HMG-CoA reductase inhibitors have been shown to inhibit SMC proliferation in vitro (9), the mechanism(s) by which they inhibit cell growth is not known. The HMG-CoA reductase inhibitors not only inhibit cholesterol synthesis, but also, inhibit the synthesis of important isoprenoid intermediates such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP).…”

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confidence: 99%

3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27

Laufs¹,

Marra²,

Node

et al. 1999

Journal of Biological Chemistry

372

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The mechanism by which platelet-derived growth factor (PDGF) regulates vascular smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 M), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 ؎ 5, 50 ؎ 3, and 48 ؎ 3%, respectively. This correlated with a 20-fold increase in p27Kip1 without changes in p16, p21 Waf1 , or p53 levels compared with PDGF alone. Since Ras and Rho require isoprenoid modification for membrane localization and are implicated in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up-regulation of p27Kip1 and inhibition of Rho but not Ras membrane translocation by Sim were reversed by geranylgeranylpyrophosphate, but not farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of dominant-negative N19RhoA mutant increased p27Kip1 and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27Kip1 and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27Kip1 by Rho GTPase mediates PDGF-induced SMC DNA synthesis and suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors on the vascular wall.

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Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase

Cited by 209 publications

References 40 publications

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

Acute Onset and Worsening of Diabetes Concurrent with Administration of Statins

3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27

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