Statins’ Coat of Many Colors Receives Yet Another Hue
Authors: Michael S. Goligorsky, Wenhui Wang
Journal: Journal of the American Society of Nephrology (2004)

With cardiovascular disease (CVD) being the ultimate cause of half of all deaths in the population of the developed countries (1), the dimensions of this modern epidemic can be readily appreciated. Among patients with chronic renal disease, the statistical figures are even more staggering, with an approximately 20-fold increased risk of CVD mortality, compared with the age-matched general population, by and large linked to accelerated atherosclerosis (2,3). There is a well established association between hypercholesterolemia and atherosclerosis (4). On average, 50% to 70% of patients with chronic renal disease and transplant recipients exhibit hypercholesterolemia, elevated LDL, and hypertriglyceridemia (5). The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors (statins), inhibiting the synthesis of L-mevalonic acid, a precursor of cholesterol, have been firmly established as the therapy of choice for hyperlipidemia. Numerous clinical trials (reviewed in (6)) established that statins reduced risk of cardiovascular events in both primary and secondary prevention settings. Unexpectedly, their beneficial effects could not be explained entirely by the mere reduction in LDL cholesterol. A recent analysis of published clinical trials unequivocally demonstrated the effect of statins on nonlipid serum markers associated with CVD, e.g., level of C-reactive protein homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, platelet aggregation, and, possibly, LDL cholesterol oxidation (7). In the course of the past decade, clinical studies have repeatedly emphasized the actions of statins that are unaccounted for by their lipid-lowering effects. Specifically, (1) the WOSCOP and CARE trials showed that patients with comparable level of serum cholesterol fared better on statin compared with placebo therapy; (2) despite comparable reduction in serum cholesterol achieved with various lipid-lowering therapies, statin-treated patients exhibited much lower risk of myocardial infarction; (3) the FATS trial showed that, in the face of a marginal 0.7% regression of angiographically detected atherosclerotic lesion, statins decreased the incidence of coronary events by 70%; and (4) the MIRACL trial showed reduction of recurrent coronary ischemia already within the first 4 mo of therapy, a time frame too short to explain the benefit exclusively by the lipid-lowering effect of statins (reviewed in (8)). These observations set the stage for systematic investigation of alternative products suppressed by HMG-CoA reductase inhibition as potential mechanism or mechanisms of cholesterol-independent action of statins. Inhibition of HMG-CoA reductase, apart from blocking the synthesis of cholesterol, results in the depletion of other downstream products of mevalonate metabolism: isoprenoids, such as farnesylpyrophosphate and geranylgeranylpyrophosphate (9). These products are critical elements of the posttranslational modification and subcellular localization of such ubiquitous signaling proteins as G-proteins, small guanosine triphosphate (GTP)-binding protein Ras, and Rho family members. One of the important consequences of this inhibition is stimulation of endothelial nitric oxide synthase (eNOS) expression (10,11). The universal nature of these messengers explains in part the pleiotropic action of statins. In this vein, inhibition of Rac-1-mediated oxidative stress is believed to be in part responsible for improvement of endothelial dysfunction, and for reduced oxidative modification of LDL in statin-treated cholesterol-fed rabbits (12,13). In addition, statins have been found to interact with the I domain of leukocyte function antigen (LFA)-1, thus inhibiting the integrin and consequently leukocyte-endothelial cell interactions (14). Another recently identified, unexpected action of statins is the recruitment of endothelial progenitor cells, which occurs via the PI3-kinase/Akt pathway (15,16). These and other pleiotropic effects of statins, their “coat of many colors,” target various pathways engaged in the development of vascular dysfunction and progression of atherosclerosis, as schematically summarized in Figure 1.Figure 1.: Vascular effects of statins. This summary compiles only well documented effects of statins that account for their pleiotropic effect on the vasculature. Of note, neither nonvascular effects (e.g., suppression or induction of proteinuria, prevention of osteoporosis) nor the adverse side effects of statins are presented here, because these subjects are beyond the focus of this summary. The findings presented in Kuhlmann et al. (17) are double-framed. CRP, C-reactive protein; AT-1, angiotensin-1; ET-1, endothelin-1; tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1.The current issue of the Journal brings about yet another mode of statin action, i.e., opening of calcium-activated potassium channels (17). The main line of investigations presented in it showed that application of a statin at the concentration of 10 to 30 nM to cultured endothelial cells resulted in the increased open probability of this channel, an effect that required a remarkably short latency of 15 to 20 min and lasted for more than 30 min, was mevalonate and iberiotoxin inhibitable and could be reproduced in the inside-out patches, thus demonstrating a novel direct target of cerivastatin. No other statins were examined, so we do not know whether this is a class effect or typical of only this compound. At any rate, the opening of this channel was responsible for hyperpolarization of endothelial cells, an effect that may have important functional implications. Hyperpolarization of these cells has been shown to increase the driving force for calcium entry leading to elevation of the cytosolic calcium concentration, the stimulus for eNOS activation (18,19). Indeed, the authors showed elevation of cytosolic calcium concentration and used an NO-sensitive fluorophore to demonstrate an increase in NO generation in endothelial cells exposed to this statin. This was further confirmed by the demonstration of increased production of cyclic guanosine monophosphate (GMP), all suggestive of the activation of the constitutive calcium-dependent NOS. This finding may complement the previous observation of an increased eNOS abundance via increase in the half-life of its mRNA (11) by providing a rapid mode of activation via calcium signaling. The undoubted importance of this observation may in part explain the strong antiatherogenic action of NO. However, the precise molecular mechanism for the observed channel opening by cerivastatin remains unclear. One cannot discount the traditional cholesterol-dependent route leading to the rapid depletion of cholesterol in lipid-rich domains of the plasma membrane and the subsequent activation of the enzyme (reviewed in (20)). Indeed, statins have been suggested to reduce caveolar abundance (21). For such a mechanism to be operant, the rate of cholesterol trafficking and exchange would have to be quite impressive to account for the depletion of membrane cholesterol within 15 min. Another potentially beneficial consequence of endothelial hyperpolarization in vivo could be attributed to the hyperpolarization of the adjacent vascular smooth muscle cells, via a hyperpolarizing factor or direct coupling, leading to vasorelaxation. Investigating whether this mechanism is operant represents a reasonably straightforward task, which, we hope, these investigators will pursue. An additional finding presented in this article, namely that of endothelial cell proliferation stimulated by statins, will also require verification via an in vivo system. Several observations described in the article are difficult to interpret. Among them is the potentiation of acetylcholine effect on NO production by cerivastatin. Diverse mechanisms could be involved, and this action may not necessarily be dependent on membrane potential alone. In addition, these results remain to be reconciled with the previous work by the same investigators, where they demonstrated that oxidized LDL activates the same potassium channel (22). It is difficult to comprehend how such diametrically opposite stimuli could lead to the same end effect. At any event, this publication raises many important issues, some of which are summarized below. First, it needs to be examined whether the dysfunctional endothelium, the prodrome of diverse CVD, responds to statins in the same way as described for the intact cultured cells. Second, observations related to endothelial cell proliferation and the possibility of hyperpolarization of endothelial cells leading to hyperpolarization of vascular smooth muscle need to be tested in vivo. And finally, it is worth investing effort in discovering the molecular mechanism or mechanisms of statin’s opening the potassium channel: is it cholesterol dependent, or does the effect actually add a hue to the Technicolor coat of statins?