Pleiotropic Effects of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors: Candidate Mechanisms for Anti-Lipid Deposition in Blood Vessels

Abstract

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.

Pleiotropic effects: Should statins be considered an essential component in the treatment of dyslipidemia?

“…There are, however, additional effects of statins that appear to be independent of LDL-C. Best described is the well-known effect of nitric oxide (NO) on the inhibition of platelet aggregation. Statins cause an upregulation of endothelial NO synthase, leading to increased NO at the vascular endothelium and a subsequent vascular dilation and diminution of platelet adhesion [12,13]. This appears to be an effect independent of lipid modification.…”

“…This has been studied in in vitro and animal models but remains difficult to measure in clinical studies [12]. Clinical trials have shown, however, a significant reduction in fibrinogen levels with long-term statin therapy, increased levels of tissue-type plasminogen activator, and a reduction in the phospholipid content of platelet membranes [15,16].…”

“…The purpose of this article is to examine the possible means by which statins reduce CVD risk independent of their serum lipid-regulating effects, including the decrease of LDL-C and the increase of HDL-C. Purported mechanisms for statin influence include antithrombotic and anti-inflammatory effects, inhibition of oxidation, plaque stabilization, and endothelial wall relaxation resulting in lower intra-arterial pressure and increased blood flow [11][12][13]. A summary of pleiotropic effects is seen in Table 1.…”

Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

“…While the effects of statins on plasma lipid levels are well described, the actual mechanisms by which these and other effects are obtained are not always clear (2). Statins have pleiotropic effects at the physiological level (e.g., depression, insomnia, neuropathy, antiinflammatory, and antiatherogenic effects) as well as at the cellular (e.g., interference with lysosomal functions) and biochemical levels (e.g., reduced isoprenylation of proteins and inhibition of GTPases) (3)(4)(5)(6). Furthermore, statins are increasingly being considered as anti-cancer drugs because of their effects on the RAS superfamily of GTPases (1) and have recently proven protective against heart failure in patients where cholesterol levels are not elevated (7).…”

Caffeinated Coffee Blunts the Myocardial Protective Effects of Statins against Ischemia–Reperfusion Injury in the Rat

“…Moreover, both dipyridamole [32] and cilostazole [50] augment the infarct-size limiting effect of low-dose ATV by augmenting myocardial levels of adenosine. In addition to their protective effects against ischemia-reperfusion injury, Akt and eNOS activation have central roles in mediating other pleiotropic effects of statins, such as vasodilation, antiinflammatory effects, anti-platelet effects, anti-atherosclerosis effects, mobilization of endothelial progenitor cells and neovascularization [51][52][53]. Thus, heavy consumption of CC may deprive patients from these potentially important non-lipid lowering effects of statins.…”