Isoprenoids as mediators of the biological effects of statins

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are potent inhibitors of cholesterol biosynthesis.Several large clinical trials have demonstrated the benefits of cholesterol lowering with these agents in the primary and secondary prevention of coronary heart disease.The overall clinical benefits observed with statin therapy, however, appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels.Recent experimental and clinical evidence indicates that some of the cholesterol-independent, or so-called pleiotropic, effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response in the vascular wall.Many of these cholesterolindependent effects reflect statins' ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules.In particular, the inhibition of small GTP-binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent upon isoprenylation, may play an important role in mediating the biological effects of statins. Pharmacological properties of statinsStatins bind to HMG-CoA reductase at nanomolar concentrations, leading to competitive displacement of the natural substrate, HMG-CoA, which binds at micromolar concentrations (1).In addition, inhibition of cholesterol biosynthesis is accompanied by an increase in hepatic LDL receptor, which promotes uptake and clearance of cholesterol from the bloodstream.While all statins inhibit hepatic HMG-CoA reductase to varying degrees, important structural differences exist among the statins that distinguish their lipophilicity, half-life, and potency (2).For example, one of the more potent newer statins, rosuvastatin, is relatively hydrophilic and has a greater number of bonding interactions with the catalytic site of HMG-CoA reductase compared with mevastatin, fluvastatin, simvastatin, cerivastatin, and atorvastatin (1, 3).The lipophilic statins would be expected to penetrate cell membranes more effectively than the more hydrophilic statins, causing more side effects but, at the same time, eliciting more pleiotropic effects.However, the observation that hydrophilic statins have pleiotropic effects similar to those of lipophilic statins calls into question whether there are really any cholesterol-independent effects of statins.Indeed, recent evidence suggests that some of the cholesterol-independent effects of these agents may be mediated by inhibition of hepatic HMG-CoA reductase, leading to subsequent reduction in circulating isoprenoid levels (4).This hypothesis may help explain why hydrophilic statins such as pravastatin and rosuvastatin are still able to exert cholesterol-independent benefits on the vascular wall without directly entering vascular wall cells.In this respect, the word "pleiotropic" probably does not reflect the hepatic versus nonhepatic effects of these agents. Clinical trials with statinsBecause serum cholesterol level is strongly associated with coronary heart disease (5), it has been generally assumed that cholesterol reduction by statins is the predominant, if not the only, mechanism underlying their beneficial effects in cardiovascular diseases.However, subgroup analysis of large clinical trials such as the 4S, WOSCOP, CARE, and HPS suggests that the clinical benefits of statins are not associated with base-line cholesterol levels or the degree of cholesterol reduction (6-9).Furthermore, in angiographic trials, clinical improvements with statins far exceed changes in the size of atherosclerotic lesions (10).It is quite likely that cholesterol lowering in these longterm trials stabilized atherosclerotic plaques and made them less prone to rupture.However, in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, statins reduced recurrent ischemic events within 16 weeks following acute coronary ischemia (11).Although the serum LDL-cholesterol was decreased by 40%, this time frame was probably far too rapid for appreciable changes in lesion size and plaque stability to occur as a consequence of cholesterol reduction.An intriguing but perplexing result of large clinical trials with statins is the reduction in ischemic stroke (12).Although myocardial infarction is closely associated with serum cholesterol levels, neither the Framingham Heart Study nor the Multiple Risk Factor Intervention