title: Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities.
abstract: Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating PPARγ and endothelial NOS signaling pathways. Moreover, the PPARγ-independent anti-oxidant and lipid-lowering effects of rosuvastatin might additionally play a role in the improvement of vascular endothelial function.
authors.affiliation: Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa, 125 055, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Kathuria
authors.forename: Nanjaian
authors.initials: N
authors.lastname: Mahadevan
authors.forename: Pitchai
authors.initials: P
authors.lastname: Balakumar
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D009538:Nicotine / Q000009:adverse effects*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D012907:Smoking; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides; D014652:Vascular Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D014026:Nicotiana
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D009566:Nitrates; D009573:Nitrites; D047495:PPAR gamma; D011743:Pyrimidines; D013449:Sulfonamides; D013481:Superoxides; D009569:Nitric Oxide; D009538:Nicotine; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III