title: In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-κB and upregulation of pAkt-e-NOS.
abstract: Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg·kg·d, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, ±LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-α level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IκB kinase/nuclear factor-kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IκB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis.
authors.affiliation: Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Malik
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Sharma
authors.forename: Saurabh
authors.initials: S
authors.lastname: Bharti
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.forename: Jagriti
authors.initials: J
authors.lastname: Bhatia
authors.forename: Tapas Chandra
authors.initials: TC
authors.lastname: Nag
authors.forename: Rajiv
authors.initials: R
authors.lastname: Narang
authors.forename: Dharamvir Singh
authors.initials: DS
authors.lastname: Arya
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D002316:Cardiotonic Agents; D016328:NF-kappa B; D011804:Quinolines; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C108475:pitavastatin