statins or 3-hydroxy - methylglutaryl coenzyme - a ( hmg - coa ) reductase inhibitors are a potent class of cholesterol synthesis inhibitors and an established therapy for primary and secondary prevention of coronary artery diseases .
several large studies confirmed reduction in cardiac mortality and morbidity through the treatment with statins .
these clinical benefits were reported to be majorly due to lowering of low - density lipoprotein cholesterol ( ldl - c ) . a linear relationship between ldl - c and cardiovascular ( cv ) event rates
the study showed landmark reduction in the rate of major coronary event by over 50% after use of statins .
this reduction was associated with 2-mmol ( 78 mg / dl ) reduction in ldl - c levels .
later several other studies such as the cholesterol treatment trialists meta - analyses , the treating to new target , heart progression study ( hps ) , cholesterol and recurrent events ( care ) trial and long - term intervention with pravastatin in ischaemic disease ( lipid ) studies also confirmed the findings of 4s . accumulating evidence have suggested that statins , in addition to ldl - c lowering , exhibited properties of plaque stabilization and endothelial homeostasis ; anti - inflammatory , antioxidant , anti - proliferative and immunomodulatory effects ; normalization of sympathetic outflow ; and prevention of platelet aggregation .
pleion ,  which means more , and  tropy  meaning response or stimuli .
though pleiotropic effects are defined as a single gene affecting multiple systems or determining more than one phenotype , lately statin pleiotropy is referred as statins exerting multiple pharmacological activities .
the pleiotropic effect is the class effect of statins and is exhibited by all statins acting on non - hepatic tissues , including hydrophilic pravastatin , which penetrates poorly through the cell membranes of non - hepatic cells .
the rapidity with which statins produce beneficial effects has suggested involvement of mechanisms other than its lipid - lowering activities . over the last more than 10 years
, several clinical trials indicated that the benefits of statins extend beyond their effects on cholesterol , supporting the theory of  statin pleiotropy  [ table 1 ] .
clinical studies elucidating statin pleiotropy the program on the surgical control of the hyperlipidemias ( posch ) study reported the benefits of cholesterol lowering after partial ileal bypass surgery after almost 10 years , whereas most statin trials showed benefits at much earlier time points ( e.g. , within 5 years ) . comparing benefits after 5 years for all lipid - lowering trials ,
non - statin trials no longer were aligned to the same cholesterol : mortality risk reduction slope , whereas all statin trials aligned to this slope . in the posch study , that the 34% reduction in ldl - c within the first 3 months post ileal surgery was although earlier unnoticed could be explained by additional non - lipid effects of statins . in the west of scotland
coronary prevention study study , cox regression analyses of data highlighted that pravastatin treatment decreased ldl - c down to 24% and further reducing ldl - c levels did not show additive any benefit , and such phenomenal reduction in coronary heart disease risk was surprising in the pravastatin - treated group as such benefits could not be expected with decrease in ldl - c within this range .
this strongly supported non - lipid - lowering theory of statins . in another statin trial with 3000 subjects with unstable angina or non - q - wave acute myocardial infarction ,
aggressive treatment with statins effectively reduced recurrent ischemic events within 16 weeks after acute coronary events , reduced serum ldl- by 40% and relative risk by 16% . according to the investigators , this period was too short to expect changes in lesion size and plaque stability of such magnitude .
therefore , it was assumed that these early changes were due to the direct cellular effects on the vascular wall and improvement of endothelial function with statins . other studies that suggested the involvement of a non - lipid - lowering pleiotropic mechanism of statins
were large prospective trials , such as the hps and anglo - scandinavian cardiac outcomes ( ascot ) trials .
these studies demonstrated that relative risk reduction with statin treatment was independent of baseline lipid values .
the hps trial reported that absolute benefits were related directly to the individual vascular risk of the subjects .
patients with low hdl - c and high vascular risk , such as subjects with diabetes , significantly benefited from statin therapy possibly through lipid - independent mechanisms . in 2003 ,
, reported a randomised trial with hypertensive subjects ( n = 10,305 ) with > 3 cv risk factors .
the subjects received either atorvastatin 10 mg / day or placebo and their total cholesterol level was measured to be < 250 mg / dl .
the study was halted after a median follow - up of 3.3 years as there was a 36% reduction in the risk of myocardial infarction and fatal coronary heart disease .
these very early benefits with large reduction in coronary heart disease events were incredible and highlighted the involvement of mechanisms other than the lipid - lowering effects of stains .
this was supported by earlier studies such as the myocardial ischaemia reduction with aggressive cholesterol lowering study ( miracl ) and the pravastatin or atorvastatin evaluation and infection therapy trial ( prove - it ) where early clinical benefits were seen in subjects with coronary heart disease .
this rapid time course of event reduction in high - risk subjects with recurrent coronary ischemia suggested non - lipid - lowering effects . in 2006 , vyas et al .
, reported over 35% reduced risk of sudden cardiac death or ventricular arrhythmia development due to the plaque - stabilizing effect of statins , increased coronary blood flow and microvascular myocardial perfusion . in 2004 , cannon et al . , reported the prove - it trial , comparing the effect of intensive therapy with atrovastatin ( 80 mg ) daily versus moderate therapy with pravastatin ( 40 mg / day ) in 4162 subjects with acute coronary syndrome .
the authors reported that subjects were benefitted from intensive therapy than standard therapy , leading to separation of event curves within 3 weeks of treatment .
also , a decrease in hazard ratio was apparent as early as 6 months from treatment . in a sub - study of the prove - it trial , gibson et al .
, in the year 2009 reported the benefit of intensive statin therapy in clinical outcomes in subjects undergoing percutaneous coronary intervention for acute coronary syndrome . in 2007 , patti et al . , reported a randomized trial where 12-h pretreatment with 40 mg / day atorvastatin prior to coronary angioplasty showed improvement in clinical outcomes in subjects with acute coronary syndrome
no reduction ldl - c in levels are commonly observed , suggested that the anti - inflammatory and pleiotropic properties of statins may be of clinical importance . in 2009 ,
an observational study showed that statin users hospitalized for acute coronary syndrome were not only at a lower risk of developing in - hospital atrial fibrillation but also had a significantly lower risk of developing ventricular arrhythmias , cardiac arrest and/or death . in these subjects ,
intensive statin therapy had reduced the risk of major adverse cv events compared with moderate - dose statin therapy .
the reduction in the incidence of target vessel revascularization was independent of ldl - c and c - reactive protein ( crp ) lowering , suggesting the statin pleiotropic effect of high - dose therapy .
scientists have been intrigued with the magnitude- and timing - reduced cv events in some clinical trials and asserted that these rapid effects mediated by statins could not be explained solely on the basis of the lipid - lowering mechanism of statins .
high - sensitivity c - reactive protein ( hscrp ) is a non - specific marker of inflammatory diseases , and has been recognized as an independent risk predictor of cardiovascular diseases .
several studies have demonstrated lowering of hscrp upon treatment with statins and this effect was independent of lowering of ldl - c . in patients with high crp values , higher coronary deaths occurred in spite of low ldl - c levels . the air force / texas coronary atherosclerosis prevention study reported lowering of crp values through treatment with lovastatin , and improvement in cardiac outcomes was achieved with lowering of crp levels independent of ldc - c levels . in 2005 , nissen et al . , reported the existence of an independent correlation between low levels of crp and atheroma progression rate from a post - hoc analysis of data of a clinical study . according to the authors , regression of atheroma size was more rapid and significant with greater reduction in crp levels . however , less regression in atheroma size was observed despite greater reduction in ldl - c levels . in the primary prevention also
treatment with statin benefitted patients with high hscrp levels and low ldl - c levels and other cv risks .
subjects in the early or mild stages of heart failure benefitted from statins and the benefits were reported to be due to anti - inflammatory effects and improvement in endothelial function with statin treatment .
the presence of inflammatory components in mediating cv diseases were supported by a retrospective study , the corona ( controlled rosuvastatin multinational trial in heart failure ) trial , and patients benefitting from lowering of hscrp levels suggested a non - lipid effect of rosuvastatin .
the finding was further confirmed by the multicenter cosmos ( coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in japanese subjects ) trial .
these trials with rosuvastatin showed significant reduction in plaque volume after treatment with rosuvastatin independent of ldl - c reduction , suggesting non - lipid - lowering effects . in a double - blind study with 58 subjects with coronary artery disease , comparable reduction in ldl - c occurred through treatment with high- ( 80 mg / day ) than low - dose atorvastatin ( 10 mg / day ) plus ezetimibe ( 10 mg / day ) .
statins are known to lower cholesterol by reversibly inhibiting hmg - coa reductase , the well - known and widely established mechanism of action of statins .
inhibition of cholesterol synthesis occurs as a result of prevention of mevalonate from producing hmg - coa , since mevalonate is not an immediate precursor of cholesterol synthesis and also acts as precursor for several other key molecules needed for normal functioning of cellular processes .
in addition to cholesterol synthesis , mevalonate is required for production of non - steroidal isoprenoid intermediates such as the farnesyl pyrophosphate , geranylgeranyl pyrophosphate , isopentanyl adenosine , dolichols and polyisoprenoid side chains of ubiquinone and heme - a .
these isoprenoid intermediates are integral to the post - translation modification and activation of several intracellular / signaling proteins such as the -subunit of heterotrimeric g - proteins ; heme - a ; nuclear lamins ; and small gtp - bound protein ras and ras - like proteins such as rho , rab , rac , ral or rap .
post - translational isoprenylation , that is , attachment of isoprenoid chains helps these proteins in their covalent attachment , sub - cellular localization and intracellular trafficking .
both ras and rho proteins switch from their gdp - bound inactive state to the gtp - bound active state [ figure 1 ] . these signaling proteins play an indispensable role in multiple cellular processes  cell signaling , cell differentiation and proliferation , myelination , cytoskeleton dynamics and endocytotic / exocytotic transport [ figure 2 ] .
rho protein cycles between a cytosolic , inactive gdp - bound and an active , membrane , gtp - bound state .
inhibition of mevalonate synthesis by statins prevents membrane targeting of rho and its subsequent activation of rock .
this cycle is controlled by several cofactors , including guanine nucleotide exchange factors , gtpase - activating proteins , and guanine nucleotide dissociation inhibitors .
an important step in the activation of rho gtpases is posttranslational isoprenylation , which allows translocation of rho to the cell membrane and subsequent activation mevalonate pathway for cholesterol biosynthesis showing the effects of inhibition of hmg - coa reductase by statins .
statins decrease the isoprenylation of signaling molecules , which leads to modulation ( [increase]/[decrease ] ) of various signaling pathways .
enos : endothelial nitric oxide synthetase ; et-1 : endothelin-1 ; etc : electron transport chain ; nadph : nicotinamide adenine dinucleotide phosphate ( reduced ) ; pai-1 : plasminogen activator inhibitor-1 ; t - pa : tissue - type plasminogen activator statins have been reported to prevent isoprenylation of rho- and rho - associated kinases ( rock ) at doses that were used to lower ldl - c levels .
rho / rock are involved in controlling important functions such as regulation of contraction , migration and adhesion of vascular smooth muscle cells .
statins by inhibiting rho / rock activation increase the bioavailability of nitric oxide ( no ) . the rac protein has been involved in cardiac hypertrophy , actin cytoskeleton remodeling and generation of reactive oxygen species , and statins benefit by inhibiting rac1 .
inactivation of rho by statins was reported to upregulate peroxisome proliferator - activated receptor ( ppar ) expression and induce ppar- transcription activity in macrophages , and inhibit lipopolysaccharide .
matrix metalloproteinases ( mmps ) are zinc - dependent endopeptidases that promote angiogenesis , intimal proliferation , vessel wall remodeling and extracellular matrix degradation through enhanced migration of vascular smooth muscle cells .
the role of rho / rock pathway in the secretion of mmp-2 through stimulation of endothelin-1 and angiotensin - ii has been confirmed with use of small interfering rna and the rock pathway inhibitor , y-27632 , which inhibited mmp-2 release .
statins decrease inflammatory cells in atherosclerotic plaques and increase plaque stability through combined reduction of lipids , macrophages and mmps .
other cellular molecules inhibited by statins include nuclear factor-b ( nf-b ) , monocyte chemoattractant protein-1 and hscrp . under normal physiological conditions , nf - kb resides in the cytoplasm bound with inhibitor i - kb ( ib ) . in response to inflammatory stimuli ,
the nf - kb then translocates into the nucleus and induces the expression of inflammatory cytokines , monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 .
statins decrease the levels of reactive oxygen species and prevent dislocation of ikb from nf - kb , resulting in inactivation of nf - kb .
statins have been reported to reduce the expression of monocyte chemoattractant protein-1 , which lowers the interaction between monocytes and the vascular wall , monocyte chemotaxis , and growth and proliferation of macrophages .
antigen - presenting cells express major histocompatibility complex - ii constitutively , and its expression in human endothelial cells and monocytes increases in the presence of interferon-. various statins reduce the expression of major histocompatibility complex - ii on antigen - presenting cells , leading to decreased major histocompatibility complex - ii - mediated activation of t - cells .
in addition , statins reduce the production of various inflammatory markers such as tumor necrosis factor-  , interleukin-1 and chemotactic cytokines .
statins were reported to disrupt the oxidative stress / inflammatory cycles by decreasing lipid peroxidation and release of inflammatory mediators .
statins improve endothelial function by inhibiting the isoprenylation of rac and rho , and activation of the rock pathway .
inactivation of the rock pathway stabilizes the mrna of endothelium - derived nitric oxide synthase ( enos ) and activates the akt / pi3k cascade , leading to high enos activity , increased no production and bioavailability .
protein kinase akt has been associated with improvement of myocardial aerobic metabolism and increase in the levels of angiopoetine ( protein growth factor ) , which accelerate the process of angiogenesis .
inactivation of the ras signaling pathway was associated with prevention or reversal of cardiac remodeling in humans . in a preclinical study ,
atorvastatin reduced the synthesis of collagen , -1-procollagen mrna expression and expression of profibrotic peptide connective tissue growth factor in cell cultures of rat and human cardiac fibroblasts .
rosuvastatin administration was reported to decrease the levels of tnf- and mmp-2 and increased the circulating levels of bone marrow - derived stems cells .
statins also have inhibitory effects on release of mmp-1 and mmp-3 from macrophages and endothelial cells , and modulate remodeling processes .
in endothelial cells , statins activate protein kinase akt leading to stimulation of enos activity , increased no synthesis and neoangiogenesis . in the central nervous system , statins regulate sympathetic and vagal outflow by increasing endothelial no synthesis , and reduce the expression of angiotensin - ii and endothelial receptors .
statins by normalizing sympathetic outflow showed beneficial effects in hypertensive patients with a history of mi and cerebral ischemia .
statins attenuate the cytokine - mediated proliferation of vascular smooth muscle cells in coronary artery smooth muscle cells , arrest the cell cycle between g1s phase transitions and inhibit smooth muscle cell proliferation through modulation of ras and rho activity .
atorvastatin inhibited serotonin - induced mitogenesis and migration by inhibiting gtp - rhoa formation in pulmonary artery vascular smooth muscle cells , which was reversed by geranylgeranyl pyrophosphate but not farnesyl pyrophosphate .
the anti - platelet and antithrombotic activities of statins have been attributed to reduction of thromboxane a2 , tissue factor expression and ppars . in heart failure
statins activate phosphoinositide-3 kinase and akt , and increase the circulating levels of bone marrow - derived endothelial progenitor cells , which may contribute to improved cardiac regeneration and/or repair . in 2012 , bouitbir et al . , reported statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities .
mitohormesis is defined as a pre - conditioning or adaptive response of mitochondria to low levels of oxidative stress induced by physical exercise , reduced caloric uptake and glucose restriction .
this pleiotropic effect of statins was attributed to increased resistance / stress defense against higher levels of oxidative stress and damage to mitochondria and cardiac tissues .
use of antioxidants prevented statin - induced mitohormesis since antioxidant vitamins had decreased the clinical benefits of the simvastatin 
niacin combination in subjects with coronary artery diseases and low levels of hdl - c in the study by brown and co - workers .
therefore , some of the cardioprotective mechanisms of statins could be attributed to statin - induced mitohormesis .
treatment with simvastatin has been reported to reverse the pulmonary vascular effects of cigarette smoke , including pulmonary hypertension , smoke - induced emphysema , smoke - induced small arterial remodeling and emphysema in guinea pigs exposed to cigarette smoke for 6 months . in cancer
, preclinical studies have shown anti - proliferative , pro - apoptotic , anti - invasive and radiosensitizing properties of statins .
various lipophilic statins such as lovastatin , simvastatin and fluvastatin exerted direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes , indicating potential use of statins in breast cancer . in 2008 , bifulco et al .
, suggested that statins may have potential to treat various other neurological disorders , including alzheimer 's disease , parkinson 's disease , multiple sclerosis and primary brain tumors as antioxidant , anti - inflammatory , anti - platelet activities and effects on the nitric oxide synthase system have been confirmed previously . in vitro studies , including a few animal studies , have suggested that statins may increase bone mass by enhancing bone morphogenetic protein-2-mediated osteoblast differentiation and activity .
in addition , statins also exerted beneficial effects in rheumatoid arthritis by inhibition and downregulation of these cytokines and chemokines . in 2009 , glynn et al .
, reported an analysis of the jupiter , which showed that rosuvastatin nearly halved the risk for symptomatic venous thromboembolism vte in apparently healthy patients and the effects were ascribed to the pleiotropic effects of statins .
a recent meta - analyses including one randomized and nine observational trials was conducted on nearly 1 million people who were on statin therapy .
the results showed a 32% decrease in the risk of vte , 41% decrease in deep vein thrombosis and 30% decrease in pulmonary embolism . in women with polycystic ovary syndrome ,
statins have been reported to directly or indirectly block oxidative stress - mediated increase in thecal interstitial cell proliferation , steroidogenesis and insulin resistance . in seasonal and avian h5n1
influenza , administration of statins showed modulatory activities on various cytokines and increased the levels of other potential immunomodulatory molecules .
the beneficial effect of statins in influenza was partly ascribed to their cardioprotective , anti - inflammatory and immunomodulatory effects .
a global consensus on the concept of statin pleiotropy could not be reached as yet and remains a hot topic for debate .
the pathophysiological implications of blockade of mevalonate production in the pathway leading to synthesis of cholesterol , that is , the mevalonate pathway suggested multiple mechanisms of statins . over the years , analyses of several clinical studies , including the landmark hps and ascot - lla trial , reported findings with statins that were inexplicable with the lipid - lowering mechanism alone .
the most probable mechanism of statin pleiotropy is prevention of isoprenoids synthesis as decrease in levels of circulating isoprenoids have been reported with treatment with statins .
 statins or 3-hydroxy - methylglutaryl coenzyme a ( hmg coa ) reductase inhibitors not only prevents the synthesis of cholesterol biosynthesis but also inhibits the synthesis of essential isoprenoid intermediates such as farnesyl pyrophosphate , geranylgeranyl pyrophosphate , isopentanyl adenosine , dolichols and polyisoprenoid side chains of ubiquinone , heme a , and nuclear lamins . these isoprenoid intermediates are required for activation of various intracellular / signaling proteins- small guanosine triphosphate bound protein ras and ras - like proteins like rho , rab , rac , ral , or rap which plays an indispensible role in multiple cellular processes . 
 reduction of circulating isoprenoids intermediates as a result of hmg coa reductase inhibition by statins prevents activation of these signalling proteins . 
 hence , the multiple effects of statins such as antiinflammatory effects , antioxidant effects , antiproliferative and immunomodulatory effects , plaque stability , normalization of sympathetic outflow , and prevention of platelet aggregation are due to reduction of circulating isoprenoids and hence inactivation of signalling proteins . 
 these multiple lipid - independent effects of statins termed as statin pleiotropy would potentially open floodgates for research in multiple treatment domains catching attentions of researchers and clinician across the globe . 