Statin effects beyond lipid lowering—are they clinically relevant?

The effect of statins on the mevalonate pathway. Statins inhibit conversion of HMG-CoA to mevalonate by competitive inhibition of the rate limiting enzyme HMG-CoA reductase. Herewith, statins not only inhibit the cellular production of cholesterol but also the biosynthesis of several intermediates of the mevalonate pathway (e.g. farnesylpyrophosphate and geranylgeranylpyrophosphate). These so-called isoprenoids are essential for the posttranslational modification of several proteins involved in important intracellular signaling pathways (e.g. the small GTP-binding proteins Ras and Rho). Many of these so-called pleiotropic effects have been shown to be secondary to the inhibition of the synthesis of isoprenoid intermediates of themevalonate pathway, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP)9 and, thus, are completely independent of the intracellular cholesterol biosynthesis (Fig. 1). Isoprenoids are important attachments for the post-translational modification of a multitude of proteins involved in intracellular signal transduction pathways, including small GTP-binding proteins, which play crucial roles in the regulation of cell growth and differentiation, gene expression, cytoskeletal assembly and cell motility, proteinand lipid trafficking, nuclear transport, andhost defense.10,11 Whereas geranylgeranylation is required for activation of most of these small GTP-binding proteins (e.g. Rho, Rac, Rab, Rap), only few are farnesylated (e.g. Ras).10 Another pathway affected by statins seems tobe the regulation of the activity of the enzyme cholesteryl ester transfer protein (CETP), which transfers cholesteryl ester to very-low-densitylipoprotein (VLDL) and LDL.12 With only few exceptions13 simvastatin and pravastatin decrease plasma CETP activity in normolipidemic individuals and patients with various forms of hyperlipoproteinemia.14–16 The mechanism responsible for this effect is unknown, but could mediate some of the effects of statins beyond CETP effects on lipid metabolism. Indeed, a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis has been demonstrated.17 Moreover, the presence of a common DNA variant of the CETP gene appears to predict benefit from treatment with statins in men with coronary heart disease (CHD).17 A novel lipid-independent mechanism of action for statins, which is unrelated to their inhibitory potential on HMG-CoA reductase, has been defined very recently by showing that statins may exert an antiinflammatory effect by binding to a specific site of the lymphocyte function associated antigen-1 (LFA-1) on leukocytes.18 In this study, several statin compounds prevented LFA-1-mediated adhesion and co-stimulation of lymphocytes after bindingselectively to a novel site of LFA-1. Obviously, the considerable quantity of desirable lipid-independent statin properties found in vitro and/or in animal models could easily explain the substantial cardiovascular benefits observed with these drugs in both normo- and hypercholesterolemic individuals, if also present in humans. However, little is known about the possible existence and the clinical relevance of such properties in humans (Table 1 Lipid-independent effects of the various statins in experimental (in vitro studies and in vivo animal studies) and clinical studies Clinical studies suggesting only indirect evidence for the existence of a lipid-independent statin effect are in parenthesis, whereas those representing direct evidence are listed without parenthesis. S, simvastatin; P, pravastatin; L, lovastatin; F, fluvastatin; A, atorvastatin; C, cerivastatin; M, mevastatin; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ET-1, endothelin-1; LECA, leukocyte-endothelial cell adhesion; EC, endothelial cell; LK, leukocyte; MHC-II, major histocompatibility complex class II; VSMC, vascular smooth muscle cell; MØ, macrophage; MMP, matrix metalloproteinase; TF, tissue factor; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen vascular endothelial growth factor; endothelial Lipid-independent effects of the various statins in experimental (in vitro studies and in vivo animal studies) and clinical studies Clinical studies suggesting only indirect evidence for the existence of a lipid-independent statin effect are in parenthesis, whereas those representing direct evidence are listed without parenthesis. S, simvastatin; P, pravastatin; L, lovastatin; F, fluvastatin; A, atorvastatin; C, cerivastatin; M, mevastatin; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ET-1, endothelin-1; LECA, leukocyte-endothelial cell adhesion; EC, endothelial cell; LK, leukocyte; MHC-II, major histocompatibility complex class II; VSMC, vascular smooth muscle cell; MØ, macrophage; MMP, matrix metalloproteinase; TF, tissue factor; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen vascular endothelial growth factor; endothelial Lipid-independent effects of statins on and synthesis in the endothelial Statins endothelial synthesis by which in an in and by activation statins decrease of in a of endothelial In and, thus, to a decrease in the may synthesis activation of endothelial that by eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ET-1, endothelin-1; of the major responsible for endothelial appears to be a of the endothelial enzyme endothelial nitric oxide In that statins of in endothelial by to an in production by these shown that statins exert their effects on by which by geranylgeranylation of the small GTP-binding protein to inhibition of the biosynthesis of A on involved in the of activity by that simvastatin the protein in endothelial which in to of in an in activity and Another recently mechanism by which statins may endothelial production is their effect on of which as an of activation by a with this the inhibitory effect of on observed at a effect on However, expression, which by and/or of and of the cholesterol on the inhibition of intracellular cholesterol synthesis and thus, be Moreover, of to may from endothelial cell to the also shown to the between protein and both the protein and eNOS, which are essential for the mechanism responsible for this effect is unknown, appears to to inhibit intracellular mevalonate synthesis as as in intracellular The potential clinical of these by the that treatment of with statins and function a In statins shown to be in animal models to and an by an endothelial of experimental studies in have the lipid-independent to the of protein in endothelial in to statin to be associated with of is evidence from experimental studies that endothelial is a common of statins which is independent of their on cholesterol endothelial activity is a in the of endothelial and vascular is very complex and Indeed, vascular and of vascular in to to are on a between and of the important of the is the which is in endothelial tissue found coronary that this to the associated with coronary the found to be in patients with both atherosclerosis and coronary endothelial The of in the very of coronary atherosclerosis is by studies that the of endothelial in experimental Moreover, has been shown to in and production is by statins may synthesis by as the both and simvastatin the of and the synthesis of in a and in endothelial in effect by mevalonate but not by that by the inhibitory action of statins on of the mevalonate shown that geranylgeranylation and the presence of proteins are essential for gene the that the inhibition of isoprenoid synthesis is the mechanism of action involved in the regulation of production by Moreover, the that and simvastatin not activity in endothelial in the study, an in by endothelial in to and that the of the competitive ester not the inhibitory effect of simvastatin on gene in the study, that effect of statins on synthesis of their on the of in the of endothelial and the evidence for a of to various cardiovascular disease these a possible for statins in the of disease associated with is to play a major in the of endothelial and and are involved in the of NO, to a decrease in and to endothelial recently that simvastatin the in plasma of and by the both of in associated with experimental in the of lipid lipid-independent of and a of has been shown in vitro and in In and may inhibit the of endothelial by of the small GTP-binding protein Rac, which is essential for activation in vitro and in Moreover, that both in vascular smooth muscle in vitro and in in In the in vitro this effect by the of but not that this effect by is by a of isoprenoid of the mevalonate pathway. a inhibitory effect on and for of and to hypercholesterolemic patients shown the vivo of to which to be by direct binding of the drugs to the of in a several but not the found to exert an inhibitory effect on in In the study, inhibition of with of which Moreover, simvastatin found to inhibit the of in vitro in a an effect that by not in this study, but the of small GTP-binding proteins in the intracellular signal transduction be that this effect of simvastatin is by inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway. is that and to an in the of associated with a decrease in the of the properties of statins may their effect on and The between and the vascular a crucial in the leukocyte-endothelial cell adhesion is present in and by of of adhesion such as and adhesion on the of endothelial is known that a decrease in the from endothelial is associated with an in endothelial cell adhesion A few that the to and both in a hypercholesterolemic independent of simvastatin shown to in hypercholesterolemic in a lipid-independent these by a of leukocyte-endothelial cell with simvastatin in a in which at by of Moreover, has been shown that the small GTP-binding protein is essential for adhesion of to the geranylgeranylation for activation be that statins at in by inhibition of geranylgeranylation of this these antiinflammatory effects on endothelial cell adhesion statins to exert effects on adhesion shown to inhibit between and endothelial by the of and on and of to to a significant of of which in associated with adhesion of to but not with suggesting a crucial for cholesterol of the mevalonate pathway for the inhibitory effect of statin on and has been that treatment with simvastatin is associated with of in in to with in shown to adhesion to vascular of adhesion and and inhibition of of to the statins may by various which on their HMG-CoA but are cellular cholesterol However, very a novel mechanism of which is unrelated to inhibition of found to to potential of that statins, such adhesion and co-stimulation of lymphocytes direct binding to a specific site Another antiinflammatory action for several statins is the of the production of In and pravastatin found to inhibit of in whereas in and simvastatin but not pravastatin production of and in Moreover, found that the of the of several such as and by in an in vivo of is on the of the biosynthesis of from the mevalonate In pravastatin and have been shown to inhibit the of and growth associated with inhibition in this effect associated with an of vascular protein and a in an antiinflammatory for The that of and pravastatin a of in vascular significant in their plasma potential in hypercholesterolemic the existence of such lipid-independent antiinflammatory statin effects in for the existence of lipid-independent antiinflammatory statin properties in from a a of in which simvastatin 1 the of this antiinflammatory effect of simvastatin to that of Moreover, the inhibitory effect of simvastatin on observed plasma lipid could that simvastatin has specific antiinflammatory properties beyond and pravastatin shown to of major histocompatibility complex class on various suggesting an for statins, to co-stimulation by whereas MHC-II, such as and not evidence for an for statins from a that pravastatin may exert a effect with inhibition of lymphocyte The that of protein the and a for may predict the of and of may a of the cardiovascular in has the in this in recently that has activity by that to a significant in the of several adhesion and in endothelial these also that simvastatin but not may inhibit this effect of In is experimental evidence that statins may exert a of inhibitory effects on and that their antiinflammatory potential seems to be to a considerable of cholesterol In their inhibitory effect on the of on various and the effect with on lymphocyte activity an function for this class of that effects also in humans and the of be that the antiinflammatory and properties of statins of the of these and the of are the most important of which are to with are by a a lipid few smooth muscle and in the play a in the by their to the matrix the by by production of such as matrix Statins may of cholesterol in by the of by of the synthesis of mevalonate and which are required for cholesterol In their and antiinflammatory may also to not of statins activity and simvastatin to inhibit and of the cell an effect that by the of mevalonate and and and simvastatin decrease of by and in by their inhibitory action on the In these which are to the inhibitory effect of statins protein a potential for statins that of their and of are in the of and The isoprenoids in the mevalonate pathway are required for both and In vitro studies that most statins and in a The of this effect that of mevalonate and/or isoprenoids but not that of prevented the effect of the statins shown that statins inhibit growth by of the small GTP-binding protein which is essential for also to be the of inhibition of cholesterol synthesis and inhibition of to as shown in a the effect of from patients to In this study, 1 after the to of cellular cholesterol whereas the inhibitory effect on cell growth most after the the to the to the significant of and to and a inhibitory effect has been shown for pravastatin in the of statins on but not the pravastatin may in a in an effect that is inhibition of protein with these are in vivo that and but not in a of in is for the and the various However, the of pravastatin to the statins, the effects be to in their to the of hypercholesterolemic patients are to those of of for this is an in the binding to by in a statins may inhibit by in the statins may function by the cholesterol of which various effects also in vivo and in their effect on endothelial statins may inhibit by an in independent of cholesterol In has been shown to in and to decrease activation in in vivo without cholesterol Moreover, statins decrease the of such as which are of and and may inhibit their In to their statins may also exert by of the and shown to of tissue by in a that by with mevalonate but not on of intracellular Moreover, inhibition of gene in is inhibition of the activation of nuclear a involved in the regulation of various including statins may the the recently shown to inhibit the of plasminogen activator from and endothelial the plasminogen activator from endothelial on the mechanism involved in the of potential of endothelial in a that activity and activity in a in a and In this study, the modification of the endothelial found to be to inhibition of geranylgeranylation and of cellular the of and effects observed in vitro a for statins in the of disease associated with an such as coronary the of by of is involved in both and the is a to tissue and is involved in the of in such as and the is the of some and is to be associated also with The of is very complex on the of several and to endothelial growth representing only of the complex is of the growth involved in are in patients with without and lipid with in a significant of is associated with progression and endothelial cell in suggesting a possible for in the of progression and In this have recently that simvastatin the in coronary tissue associated with experimental in a lipid-independent Another important of the are that are responsible for and also inhibit of by in vitro and in In that simvastatin of in the in a of in the of of statins inhibit endothelial cell by a of that simvastatin in experimental of plasma that the inhibitory effects of statins on of the may an effect in A mechanism of action for statins by that to an in the and the activity of endothelial in patients with are that to of and endothelial in shown that statins from the and the signaling the in of is not to the but may also in the of the important could be which and in several to such as of responsible for these the of in and simvastatin may activity and production by the protein in endothelial effect associated with the of in of and endothelial has been in statins also the not in in a significant of to In statins have the potential to both inhibit and Indeed, a on the of this statin by that statins exert a effect on both in vitro and in In endothelial of and cell and differentiation, whereas these as endothelial and endothelial cell by of statin on endothelial by the of lipid-independent In the study, in a by of and but by statin the the that vascular may a to statins also and of an in to various of and are major of and in cardiovascular activation including an in a in of and statins have been shown to inhibit and as as to various intracellular signaling pathways including of the activity of small GTP-binding proteins of the A that simvastatin of and in a of which associated with an in and the in this disease is to be function to proteins, which in to activation of intracellular signaling and of and a to the observed in forms of heart these may a for statins in the treatment and of various forms of cardiovascular disease associated with and is by the that recently to and associated with of and in a of heart simvastatin has been shown to of an effect which has been to inhibition of the as simvastatin the in intracellular associated with In pravastatin shown to the effect of that is by in a hypercholesterolemic without Moreover, as several studies that statins may exert a effect in animal models to and which is of endothelial In with these are the of a recently study, a significant of which by inhibition of with pravastatin in that the most common of heart and the observed effects of statins on and as as their properties on be that these statin if present in could a major benefit the of heart Many of the effects of statins found in vitro that are involved in of of and of and to a of and which appears to the of clinical coronary the in the statin is to that the statin effects found in the experimental also in clinical However, some statin effects shown in vitro a of in vitro have of statins in Moreover, to the clinical most in vivo animal studies have these at of statin to in models lipid are to HMG-CoA the of in vitro animal studies are to to clinical and clinical are to the clinical of the experimental However, the specific statin properties the clinical of a the Indeed, of cholesterol in in in hypercholesterolemic a may endothelial function in hypercholesterolemic an effect that is by a decrease in the in coronary endothelial function observed in hypercholesterolemic patients with without coronary atherosclerosis in to with could be to the of the statins the in statin effects in clinical of their cholesterol to and, thus, is to possible lipid-independent effects from with lipid if these effects are of the an observed statin effect (e.g. of isoprenoid intermediates to the pathways involved in the mechanism responsible for a specific statin may not be possible in the in vivo The only to effects unrelated to modification of plasma cholesterol is to the very statin effects which the after of of plasma cholesterol However, be in that that such effects in the only the existence of effects in humans by indirect by which cholesterol presence of by patients with these In a of the by in of individuals cholesterol in the to to independent of pravastatin that for the with pravastatin a to those Moreover, of the a between and observed coronary rate in the but the benefit of pravastatin by these that the with pravastatin in hypercholesterolemic men without of be by a decrease in evidence for the existence of a lipid-independent effect of statins on endothelial function in humans is by a endothelial as as in a of men with without with that in and patients with lipid statin In this study, of the in patients statins in those without Moreover, statin as the only significant of In to in vitro clinical to an effect of on plasma The for this between the of the in vitro and in vivo studies is not but be to the experimental to between the various the is by endothelial and plasma may not tissue this the associated with the of experimental studies to clinical The existence of lipid-independent antiinflammatory effects of statins in humans is the that several statins shown to plasma in vivo of their effect on Moreover, a for an antiinflammatory vivo is by from the that the coronary with pravastatin in patients with a of in those patients at the of the study, of of and shown that statin the for major associated with in patients coronary evidence that be for statin in the of coronary without but of the the relation between is is the by is by (e.g. and a activation of the which to However, the existence of lipid-independent antiinflammatory effects of statins in humans. is statin such as the inhibition of on several the of pravastatin with on activity of found in vitro also in humans as a of clinical of these that in clinical is statin treatment associated with effects in the of a to and/or are statins of benefit in patients in a of is such as in Whereas the from clinical not the presence of a effect for statins, a possible properties of statins from some clinical in heart and In heart pravastatin and the of disease and to of in a of patients in a a significant in and a a of in heart with In pravastatin the of and the of and also the of However, in these statin treatment associated with a significant the responsible for the observed Moreover, a found in the rate in of the of in a the possible properties of statins in The of statins as in vivo is also not and to in vitro that simvastatin the rate of and the of by in an effect that only in to the of cholesterol In vivo studies on the effect of statins have some studies a in treatment with various statins, found significant The for these is not have been to on the various statin variation of and such recently the of a which the effect of various statins and on in hypercholesterolemic patients with In this study, a and effect on plasma found for of the statins that statins have a a lipid-independent effect on The effect of statins on in humans is also studies the lipid with simvastatin has been shown to biosynthesis in vivo by and to vivo in patients with in a of hypercholesterolemic men with simvastatin for to not an effect on a significant in a study, which to a significant in However, to a in showing a effect in the of in plasma lipid to humans associated with a significant decrease in plasma cholesterol and cholesterol the mechanism for this effect of on the existence of a lipid-independent effect of statins on function in vivo is However, the of a inhibitory effect of statins on as present in coronary of mechanism and the that a effect has not been observed with lipid the in the and activity of found with in patients with indirect evidence for the existence of statin effects in humans. The most evidence for the existence of lipid-independent effects from small the effects of and on endothelial In the an in function after of treatment in of with an of vascular function the effect of on endothelial function in cholesterol by the presence of a statin effect in humans. In with these are of a significant in endothelial function of the in normo- a with in the of of lipid effect associated with a significant in plasma of and the of NO, that to an in In to a of by a significant decrease in plasma whereas a plasma of the and vascular cell adhesion after These representing direct evidence for the existence of lipid-independent effects in are of clinical that endothelial the very of and presence is associated with an Moreover, these effects that statins be of benefit in coronary Indeed, in the the the effects of treatment in coronary the for a which and by to after an coronary However, this benefit to a in whereas the of the not is to statins as treatment in coronary but such as the study, the and study, and the in are the of statins in this and effects of statins on progression and most of the known lipid-independent statin effects to a of progression and an in some of the statin properties found in vitro also growth and if present in humans. MØ, inhibition of in vitro has been statins the this effect to an of and the of the major of the matrix which is essential for the of the of the have to be the effect by several statins in an in be in the of However, an rate of is also found in and a potential to and a major of and the of coronary However, has to be that the in vitro effects of statins on and observed statin those with in the clinical the clinical of these is Another of a of lipid-independent statin effects is their on statins may inhibit With to the of an in may be However, the progression of atherosclerosis and the of an in may be the of the the is to to progression and In this is that inhibition of may progression and to In of the presence of a and effect of statins on in vivo is that simvastatin the of in experimental independent of cholesterol Moreover, as a effect on shown for and These drugs may at whereas inhibit in a lipid-independent However, the effect of statins on in humans is which to the about the effect of statins on the of a for the of The about potential of statins by that drugs the of several in and by an of pravastatin in the However, a recently could not an between statin and a of statin an of in These studies some of about the of this class of However, as by the of most are for the In may have some and their be several that statins may play a in In and pravastatin have been shown to inhibit cell Moreover, may in various and shown to decrease growth and in a the of on and the possible effects of statins, with are the studies have to statins a to the that statin in muscle is associated with inhibition of geranylgeranylation of specific the about of lipid-independent statin effects to the but effect of statin which has recently to the of from the However, this the of muscle statins shown to decrease in a lipid-independent a that the of patients with statins and from in plasma and of statin statin in of in these a significant in the However, the mechanism and of the in these patients to In the of the known lipid-independent effects seems tobe the that some effects of statins be be tissue statins (e.g. and the Whereas compounds cell and in cellular of pravastatin is on the presence of a specific specific mechanism seems to in but not in which statins are in synthesis in whereas pravastatin has a inhibitory effect on cellular synthesis in the the and effects on and the effect on by between statins found in cell are to the of the compounds Moreover, these in vitro properties have the the various statins also exert pleiotropic effects in Indeed, has been shown that treatment of with in a of and of of of both and pravastatin associated with a significant and of lipid in these be that the in and gene the of the lipid-independent effects observed with these statins in treatment with shown to in a whereas pravastatin a statin with not plasma cholesterol in these the effect on could not be to the statins for in vivo effects of statins is the that of but not associated with with in of plasma cholesterol with statins These that lipid-independent statin effects may also be present in is that not lipid-independent statin effects a class However, the that pravastatin and the compounds have benefit in clinical that such lipid-independent statin properties found in vitro in animal studies not in humans are their and that lipid-independent properties to effect of statins on cardiovascular the benefit observed with and compounds in clinical