Pitavastatin at low dose activates endothelial nitric oxide synthase through PI3K-AKT pathway in endothelial cells

Wang, Juyong; Tokoro, Takashi; Matsui, Koshi; Higa, Susumu; Kitajima, Isao

doi:10.1016/j.lfs.2004.12.003

Cited by 55 publications

(43 citation statements)

References 27 publications

(37 reference statements)

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“…Recent studies have shown that pitavastatin has multiple effects, such as reducing inflammation 11) and the generation of reactive oxygen species 12) , improving endothelial function 13) , increasing nitric oxide production 14) , inhibiting cell adhesion 15) , inhibiting the contraction of smooth muscle cells 16) , and promoting apolipoprotein (apo) A-production 17) . Pitavastatin has a potent lipid-lowering effect, and the reduction of LDL-C is comparable to that achieved with atorvastatin 10) .…”

Section: Discussionmentioning

confidence: 99%

Influence of Pitavastatin on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus

Yamakawa

Tajiri

Tanaka

et al. 2008

JAT

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Aim:We previously reported that glycemic control deteriorated in patients receiving atorvastatin, which is useful for the treatment of hypercholesterolemia in patients with type 2 diabetes. Pitavastatin has a strong lipid-lowering effect, comparable to that of atorvastatin, but it is unknown whether pitavastatin has an adverse influence on glycemic control. The aim of this study was to examine. The effects of three different statins (pravastatin, atorvastatin, and pitavastatin) on blood glucose and HbA1c levels in diabetic patients. Methods: We retrospectively compared glycemic control between groups receiving atorvastatin (10 mg/day, group A, n 99), pravastatin (10 mg/day, group Pr, n 85), and pitavastatin (2 mg/day, group Pi, n 95) from the start of treatment until 3 months later. Patients were excluded if the dosage of their antidiabetic drugs was changed, if their drug therapy was altered within 3 months before starting statin therapy, or if events occurred that could affect glycemic control such as hospitalization. Results: The subjects available for analysis were 74 patients from group A, 71 patients from group Pr, and 74 patients from group Pi. Arbitrary blood glucose levels increased from 147 51 mg/dL (mean SD) to 176 69 mg/dL in group A, but only changed minimally from 136 31 to 134 32 mg/dL in group Pr and from 155 53 to 154 51 mg/dL in group Pi. HbA1c increased from 7.0 1.1% to 7.4 1.2% in group A, while it was 6.9 0.9% versus 6.9 1.0% in group Pr, and 7.3 1.0% versus 7.2 1.0% in group Pi. There was no correlation between LDL-C and HbA1c (the change from baseline to 3 months) in any of the groups. Conclusion: The glycemic parameters only increased significantly in group A, suggesting that pitavastatin and pravastatin did not have an adverse influence on glycemic control in type 2 diabetic patients. J Atheroscler

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Section: Discussionmentioning

confidence: 99%

Influence of Pitavastatin on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus

Yamakawa

Tajiri

Tanaka

et al. 2008

JAT

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“…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 apoptosis of ECs, as well as on angiogenesis, is as good as that of conventional statins.…”

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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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“…Both lipophilic and hydrophilic statins have been shown to inhibit RhoA isoprenylation in human endothelial cells (9,20,22) and to increase nitric oxide (NO) production and release (7,14,15,28). Accordingly, administration of GGPP and its substrate geranylgeraniol has been demonstrated to reverse the effects of statins on endothelial cells (14,16,18,27,33). Thus statins may influence cellular function by preventing RhoA signaling (8,21,29).…”

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confidence: 99%

Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation

Bulhak¹,

Roy²,

Hedin³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Bulhak A, Roy J, Hedin U, Sjöquist PO, Pernow J. Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. Am J Physiol Heart Circ Physiol 292: H3158 -H3163, 2007. First published February 23, 2007 doi:10.1152/ajpheart.01354.2006.-Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 Ϯ 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 Ϯ 2% (P Ͻ 0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 Ϯ 2%, P Ͻ 0.01 vs. rosuvastatin) but not methanol (65 Ϯ 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 Ϯ 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium (P Ͻ 0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.hydroxymethyl glutaryl-coenzyme A reductase inhibitor; ischemiareperfusion injury; myocardium; rats HYDROXYMETHYL GLUTARYL (HMG)-coenzyme A (CoA) reductase inhibitors (statins) have been used for the treatment of hypercholesterolemia for 20 years (17). The effects of statins are mediated via blockade of mevalonate formation, which results in reduction of cholesterol synthesis. Statin treatment reduces the risk of coronary events and mortality in patients with coronary artery disease (26). These clinically benefic...

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Pitavastatin at low dose activates endothelial nitric oxide synthase through PI3K-AKT pathway in endothelial cells

Cited by 55 publications

References 27 publications

Influence of Pitavastatin on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus

Influence of Pitavastatin on Glucose Tolerance in Patients with Type 2 Diabetes Mellitus

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

Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation

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