title: Cox-2 Inhibition Protects against Hypoxia/Reoxygenation-Induced Cardiomyocyte ApoptosisviaAkt-Dependent Enhancement of iNOS Expression.
abstract: The present study explored the potential causal link between ischemia-driven cyclooxygenase-2 (COX-2) expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R) by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that H/R resulted in higher COX-2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor). Furthermore, pretreatment with NS398 (COX-2 specific inhibitor) significantly attenuated H/R-induced cell injury [lower lactate dehydrogenase (LDH) leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases-3 and TUNEL-positive cells) in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R-induced increases in proinflammatory cytokines [interleukin 6 (IL6) and tumor necrosis factor (TNFα)] and reactive oxygen species (ROS) production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS) and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt-specific inhibitor) or 1400W (iNOS-selective inhibitor) cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX-2 and that higher COX-2 expression during H/R exacerbates cardiomyocyte H/R injuryviamechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.
authors: Department of Anesthesiology, The First Hospital of Jilin University, Jilin 130021, China.
authors: Lei
authors: 0000-0002-3265-3087
authors: L
authors: Pang
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Yin
authors: Y
authors: Cai
authors: Department of Pharmacology and Pharmacy and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Eva Hoi Ching
authors: EH
authors: Tang
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Dan
authors: D
authors: Yan
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Ramoji
authors: R
authors: Kosuru
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Haobo
authors: 0000-0002-5660-7835
authors: H
authors: Li
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Michael G
authors: 0000-0001-5801-274X
authors: MG
authors: Irwin
authors: Department of Anesthesiology, The First Hospital of Jilin University, Jilin 130021, China.
authors: Haichun
authors: 0000-0002-8467-5421
authors: H
authors: Ma
authors: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Zhengyuan
authors: 0000-0002-7002-5524
authors: Z
authors: Xia
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt