Statins’ Coat of Many Colors Receives Yet Another Hue
Michael S. Goligorsky and
Wenhui Wang
Departments of Medicine and Pharmacology and Renal Research Institute, New York Medical College, Valhalla, New York.
Correspondence to Dr. Michael S. Goligorsky, Renal Research Institute, new York Medical College, Valhalla, NY 10595. Phone: 914-594-4731; Fax: 914-594-4732; E-mail: michael_goligorksy{at}nymc.edu
With cardiovascular disease (CVD) being the ultimate cause ofhalf 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 figuresare even more staggering, with an approximately 20-fold increasedrisk of CVD mortality, compared with the age-matched generalpopulation, by and large linked to accelerated atherosclerosis(2,3). There is a well established association between hypercholesterolemiaand atherosclerosis (4). On average, 50% to 70% of patientswith chronic renal disease and transplant recipients exhibithypercholesterolemia, elevated LDL, and hypertriglyceridemia(5). The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductaseinhibitors (statins), inhibiting the synthesis of L-mevalonicacid, a precursor of cholesterol, have been firmly establishedas the therapy of choice for hyperlipidemia. Numerous clinicaltrials (reviewed in (6)) established that statins reduced riskof cardiovascular events in both primary and secondary preventionsettings. Unexpectedly, their beneficial effects could not beexplained entirely by the mere reduction in LDL cholesterol.A recent analysis of published clinical trials unequivocallydemonstrated the effect of statins on nonlipid serum markersassociated 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 haverepeatedly emphasized the actions of statins that are unaccountedfor by their lipid-lowering effects. Specifically, (1) the WOSCOPand CARE trials showed that patients with comparable level ofserum cholesterol fared better on statin compared with placebotherapy; (2) despite comparable reduction in serum cholesterolachieved with various lipid-lowering therapies, statin-treatedpatients 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 coronaryischemia already within the first 4 mo of therapy, a time frametoo short to explain the benefit exclusively by the lipid-loweringeffect of statins (reviewed in (8)). These observations setthe stage for systematic investigation of alternative productssuppressed by HMG-CoA reductase inhibition as potential mechanismor mechanisms of cholesterol-independent action of statins.
Inhibition of HMG-CoA reductase, apart from blocking the synthesisof cholesterol, results in the depletion of other downstreamproducts of mevalonate metabolism: isoprenoids, such as farnesylpyrophosphateand geranylgeranylpyrophosphate (9). These products are criticalelements of the posttranslational modification and subcellularlocalization of such ubiquitous signaling proteins as G-proteins,small guanosine triphosphate (GTP)-binding protein Ras, andRho family members. One of the important consequences of thisinhibition is stimulation of endothelial nitric oxide synthase(eNOS) expression (10,11). The universal nature of these messengersexplains in part the pleiotropic action of statins. In thisvein, inhibition of Rac-1-mediated oxidative stress is believedto be in part responsible for improvement of endothelial dysfunction,and for reduced oxidative modification of LDL in statin-treatedcholesterol-fed rabbits (12,13). In addition, statins have beenfound to interact with the I domain of leukocyte function antigen(LFA)-1, thus inhibiting the integrin and consequently leukocyte-endothelialcell interactions (14). Another recently identified, unexpectedaction of statins is the recruitment of endothelial progenitorcells, which occurs via the PI3-kinase/Akt pathway (15,16).These and other pleiotropic effects of statins, their "coatof many colors," target various pathways engaged in the developmentof 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 modeof statin action, i.e., opening of calcium-activated potassiumchannels (17). The main line of investigations presented init showed that application of a statin at the concentrationof 10 to 30 nM to cultured endothelial cells resulted in theincreased open probability of this channel, an effect that requireda remarkably short latency of 15 to 20 min and lasted for morethan 30 min, was mevalonate and iberiotoxin inhibitable andcould be reproduced in the inside-out patches, thus demonstratinga novel direct target of cerivastatin. No other statins wereexamined, so we do not know whether this is a class effect ortypical of only this compound. At any rate, the opening of thischannel was responsible for hyperpolarization of endothelialcells, an effect that may have important functional implications.Hyperpolarization of these cells has been shown to increasethe driving force for calcium entry leading to elevation ofthe cytosolic calcium concentration, the stimulus for eNOS activation(18,19). Indeed, the authors showed elevation of cytosolic calciumconcentration and used an NO-sensitive fluorophore to demonstratean increase in NO generation in endothelial cells exposed tothis statin. This was further confirmed by the demonstrationof increased production of cyclic guanosine monophosphate (GMP),all suggestive of the activation of the constitutive calcium-dependentNOS. This finding may complement the previous observation ofan increased eNOS abundance via increase in the half-life ofits mRNA (11) by providing a rapid mode of activation via calciumsignaling. The undoubted importance of this observation mayin part explain the strong antiatherogenic action of NO. However,the precise molecular mechanism for the observed channel openingby cerivastatin remains unclear. One cannot discount the traditionalcholesterol-dependent route leading to the rapid depletion ofcholesterol in lipid-rich domains of the plasma membrane andthe 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 cholesteroltrafficking and exchange would have to be quite impressive toaccount for the depletion of membrane cholesterol within 15min. Another potentially beneficial consequence of endothelialhyperpolarization in vivo could be attributed to the hyperpolarizationof the adjacent vascular smooth muscle cells, via a hyperpolarizingfactor or direct coupling, leading to vasorelaxation. Investigatingwhether this mechanism is operant represents a reasonably straightforwardtask, which, we hope, these investigators will pursue. An additionalfinding presented in this article, namely that of endothelialcell proliferation stimulated by statins, will also requireverification via an in vivo system.
Several observations described in the article are difficultto interpret. Among them is the potentiation of acetylcholineeffect on NO production by cerivastatin. Diverse mechanismscould be involved, and this action may not necessarily be dependenton membrane potential alone. In addition, these results remainto be reconciled with the previous work by the same investigators,where they demonstrated that oxidized LDL activates the samepotassium channel (22). It is difficult to comprehend how suchdiametrically 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 examinedwhether the dysfunctional endothelium, the prodrome of diverseCVD, responds to statins in the same way as described for theintact cultured cells. Second, observations related to endothelialcell proliferation and the possibility of hyperpolarizationof endothelial cells leading to hyperpolarization of vascularsmooth muscle need to be tested in vivo. And finally, it isworth investing effort in discovering the molecular mechanismor mechanisms of statin’s opening the potassium channel:is it cholesterol dependent, or does the effect actually adda hue to the Technicolor coat of statins?
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