Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes

Corsini, Alberto; Raiteri, M.; Soma, Maurizio R.; Fumagalli, R.; Paoletti, Rodolfo

doi:10.1016/s1043-6618(05)80119-7

Cited by 74 publications

(35 citation statements)

References 26 publications

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“…18 This in vitro inhibitory effect was prevented by addition of mevalonate to the culture medium, indicating that cell proliferation is precluded by blockade of intracellular mevalonic acid biosynthesis. 16 ' 18 The antiproliferative property shown by some vastatins has been reported in a variety of cultured mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

“…Compactin and simvastatin inhibit smooth muscle cell growth in vitro. 16 - 18 Aggressive lipid-lowering treatment with lovastatin prevented restenosis after balloon angioplasty in hypercholesterolemic rabbits 19 and humans. 20 However, no correlations between serum cholesterol and restenosis were found in percutaneous transluminal coronary angioplasty patients.…”

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confidence: 99%

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HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

Soma

Donetti

Parolini

et al. 1993

Arterioscler Thromb

210

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The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexible collar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 ing/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36±0.04 versus 0.03±0.02). Animals treated with lovastatin (R=12), simvastatin (n=12), and fluvastatin (R=12) showed significantly less neointimal formation; I/M tissue ratios were 0.24±0.03, 0.20±0.03, and 0.17±0.03, respectively. The inhibition elicited by pravastatin (n=12, 032 ±0.03) did not reach statistical significance. or-Actin antibody immunofluorescence analysis of serial sections revealed that cells present in the hyperplastic intima were mostly myocytes. Rates of intimal myocyte proliferation were also measured by incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into replicating DNA. Immunofluorescence analysis showed that 5-bromo-2'-deoxyuridine was actively incorporated into intimal myocytes after insertion of the collar, with a labeling index (percent of labeled myocytes) of 2.15 after 14 days. Labeling indexes for pravastatin-, lovastatin-, simvastatin-, and fluvastatin-treated carotid arteries were 2.01, 1.32,1.23, and 1.20, respectively, suggesting a direct effect of vastatins on arterial myocyte proliferation. The different responsiveness shown by the vastatins tested may be attributed to the differences in their capacity to penetrate cell membranes and their potency in inhibiting the HMG CoA reductase enzyme. We conclude that the inhibition of carotid intimal myocyte proliferation by these vastatins is independent of their effect on plasma cholesterol concentrations. -11 suggesting that the hypolipidemic effect is

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

Soma

Donetti

Parolini

et al. 1993

Arterioscler Thromb

210

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“…Besides regulating cholesterol synthesis, HMG-CoA reductase plays an important role in cell proliferation as the mevalonate pathway yields both cholesterol and non-sterol metabolites (such as geranylaeraniol and farnesol) which are essential for the DNA replication (2). Pharmacological approaches have shown that simvastatin inhibits proliferation of rat smooth muscle cells (SMC) (3).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin, a potent HMG-CoA Reductase Inhibitor, inhibits the Proliferation of Human and Bovine Endothelial Cells in vitro

Sato

Ikeda

et al. 1998

J Atheroscler Thromb

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“…[2][3][4][5][6] It has been suggested that the preventive effect of statins is attributable to their cholesterol-lowering action, but there is research demonstrating that statin therapy also prevents cardiovascular events in patients with an average cholesterol level, 4 suggesting that statins prevent coronary vascular events not only through cholesterol-lowering but also through some other process. The mechanisms of these effects beyond the reduction of cholesterol, the so-called pleiotropic functions, have been gradually elucidated by a number of studies.The pleiotropic functions of statins are involved in the regulation of cell adhesion molecules and the cell cycle, 7-11 inhibition of cell growth and/or induction of apoptosis in vascular smooth muscle cells, [12][13][14] 16,17 and inhibition of vascular NAD(P)H oxidase, 18 among others. Moreover, we have reported that in experiments in dogs cerivastatin inhibited migration of ECs in vitro and intimal thickening of balloon-injured arteries in vivo.…”

mentioning

confidence: 99%

“…The pleiotropic functions of statins are involved in the regulation of cell adhesion molecules and the cell cycle, 7-11 inhibition of cell growth and/or induction of apoptosis in vascular smooth muscle cells, [12][13][14] 16,17 and inhibition of vascular NAD(P)H oxidase, 18 among others. Moreover, we have reported that in experiments in dogs cerivastatin inhibited migration of ECs in vitro and intimal thickening of balloon-injured arteries in vivo.…”

mentioning

confidence: 99%

Biphasic Effect of HMG-CoA Reductase Inhibitor, Pitavastatin, on Vascular Endothelial Cells and Angiogenesis

Katsumoto

Shingu

Kuwashima

et al. 2005

Circ J

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tatins reduce the serum cholesterol level by inhibiting 3-hydroxyl-3-methyl coenzyme A (HMG-CoA) reductase. Mega-trials have demonstrated the safety and efficiency of long-term cholesterol-lowering therapy using low-dose statin, 1 and that intervention with statins prevent cardio-and cerebrovascular events in patients with hypercholesterolemia. [2][3][4][5][6] It has been suggested that the preventive effect of statins is attributable to their cholesterol-lowering action, but there is research demonstrating that statin therapy also prevents cardiovascular events in patients with an average cholesterol level, 4 suggesting that statins prevent coronary vascular events not only through cholesterol-lowering but also through some other process. The mechanisms of these effects beyond the reduction of cholesterol, the so-called pleiotropic functions, have been gradually elucidated by a number of studies.The pleiotropic functions of statins are involved in the regulation of cell adhesion molecules and the cell cycle, 7-11 inhibition of cell growth and/or induction of apoptosis in vascular smooth muscle cells, [12][13][14] 16,17 and inhibition of vascular NAD(P)H oxidase, 18 among others. Moreover, we have reported that in experiments in dogs cerivastatin inhibited migration of ECs in vitro and intimal thickening of balloon-injured arteries in vivo. 19 With respect to angiogenesis, some researchers have show that simvastatin and cerivastatin promote collateral vessel formation in ischemic tissues of animal models. 20,21 On the other hand, these same drugs reportedly inhibited the migration and viability of ECs, and interrupted angiogenesis. [22][23][24] More recent reports indicate that simvastatin, cerivastatin and atorvastatin exert a biphasic effect on cultured ECs and angiogenesis in a dose-dependent manner. [25][26][27] "New generation" statins, which have a stronger effect on cholesterol reduction than conventional statins, have been developed and one of them, pitavastatin, exhibits a potent hypolipidemic effect in both animal and human trials. [28][29][30] At a dose of 4 mg/day pitavastatin has been shown to be equivalent to atorvastatin at a dose of 80 mg/day in reducing low-density lipoprotein in heterozygous familial hypercholesterolemia patients. 29 There are some reports of its pleiotropic effects on ECs; pitavastatin increased thrombomodulin, tissue-type plasminogen activator and nitric oxide production, and decreased plasminogen activator inhibitor 1 and inflammatory cytokine. [31][32][33][34] Moreover, pitavastatin has augmented capillary formation in the ischemic limb of an animal model. 35 These pleiotropic effects of pitavastatin are similar to those of conventional statins and so it is interesting to know whether or not the effect of pitavastatin on the migration, proliferation, and Methods and ResultsThe effects of pitavastatin on the migration, proliferation and viability of human epidermal microvessel endothelial cells (HMVECs) were examined using scratch assay, chemotaxis chamber, bromodeoxyuridin...

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Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes

Cited by 74 publications

References 26 publications

HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.

Simvastatin, a potent HMG-CoA Reductase Inhibitor, inhibits the Proliferation of Human and Bovine Endothelial Cells in vitro

Biphasic Effect of HMG-CoA Reductase Inhibitor, Pitavastatin, on Vascular Endothelial Cells and Angiogenesis

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