title: Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?
abstract: Statins are widely used in the treatment of dyslipidemia and associated cardiovascular abnormalities including atherosclerosis, hypertension and coronary heart disease. Needless to mention, statins have cholesterol-lowering effects by means of inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis. Besides cholesterol-lowering effects, statins possess pleiotropic anti-inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties, which may additionally play imperative roles in statins-mediated cardiovascular protection. However, the precise mechanisms involved in the cardiovascular defensive potential of statins have not completely been elucidated. Intriguingly, a considerable number of studies demonstrated the potential modulatory role of statins on endothelial nitric oxide synthase (eNOS), a key enzyme involved in the regulation of cardiovascular function by generating endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy of note is that vascular generation of nitric oxide has beneficial anti-inflammatory, anti-platelet and vasodilatory actions. The upregulation of eNOS by statins is mediated through inhibition of synthesis of isoprenoids and subsequent prevention of isoprenylation of small GTPase Rho, whereas statin-induced activation of eNOS is mediated through activation of phosphotidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) signals. Additionally, statins enhance eNOS activation by abrogating caveolin-1 expression in vascular endothelium. In light of this view-point, we suggest in this review that eNOS upregulation and activation, in part, could play a fundamental role in the cardiovascular defensive potential of statins. The eNOS modulatory role of statins may have an imperative influence on the functional regulation of cardiovascular system and may offer new perspectives for the better use of statins in ameliorating cardiovascular disorders.
authors.affiliation: Cardiovascular Pharmacology Division, Department of Pharmacology, Institute of Pharmacy, Rajendra Institute of Technology and Sciences, Sirsa-125 055, India. pbala2006@gmail.com
authors.forename: Pitchai
authors.initials: P
authors.lastname: Balakumar
authors.forename: Sonam
authors.initials: S
authors.lastname: Kathuria
authors.forename: Gaurav
authors.initials: G
authors.lastname: Taneja
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kalra
authors.forename: Nanjaian
authors.initials: N
authors.lastname: Mahadevan
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047492:Peroxisome Proliferator-Activated Receptors; D052250:Nitric Oxide Synthase Type III