Pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: candidate mechanisms for anti-lipid deposition in blood vessels.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are considered first-line therapeutic agents for the prevention of coronary heart disease and atherosclerotic disorders related to hypercholesterolemia. Statins inhibit lipid deposition in the aortic endothelium. Although it has been accepted that the statins are potent inhibitors of cholesterol biosynthesis in the liver and that they lower circulating cholesterol levels, several cholesterol-independent (pleiotropic) effects have been reported. The cholesterol-independent effects of statins involve normalization of the nitric oxide (NO)-NO synthase system, anti-inflammatory effects through the inhibition of cytokine/chemokine production, inhibition of vascular smooth muscle cell proliferation and migration, and inhibition of platelet thrombus formation/reduction of the thrombotic response. Some pleiotropic effects of statins may depend on the inhibition of the biosynthesis of farnesyl- and geranylgeranyl-nonsterol compounds from mevalonate in the cells. The Rho/Rho kinase pathway and the phospatidylinositol-3 kinase/Akt pathway mediate the pleiotropic effects of statins. As variations occur in absorption, metabolism, and excretion mechanisms due to the characteristics of specific statins including their hydrophilicity and lipophilicity, there are differences in the transfer mechanisms of statins into tissues. However, the pleiotropic effects occur regardless of statin hydrophilicity and lipophilicity. This review summarizes the pleiotropic effects of statins on lipid deposition in blood vessels.
Kumai
T
T
Department of Pharmacology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki-shi, Kanagawa, Japan. yakuri@marianna-u.ac.jp
Matsumoto
N
N
Koitabashi
Y
Y
Takeba
Y
Y
Oonuma
S
S
Sekine
S
S
Tadokoro
M
M
Kobayashi
S
S
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D050356:Lipid Metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases