title: Ischemic postconditioning protects the heart against ischemia-reperfusion injury via neuronal nitric oxide synthase in the sarcoplasmic reticulum and mitochondria.
abstract: As a result of its spatial confinement in cardiomyocytes, neuronal nitric oxide synthase (nNOS) is thought to regulate mitochondrial and sarcoplasmic reticulum (SR) function by maintaining nitroso-redox balance and Ca(2+) cycling. Thus, we hypothesize that ischemic postconditioning (IPostC) protects hearts against ischemic/reperfusion (I/R) injury through an nNOS-mediated pathway. Isolated mouse hearts were subjected to I/R injury in a Langendorff apparatus, H9C2 cells and primary neonatal rat cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro. IPostC, compared with I/R, decreased infarct size and improved cardiac function, and the selective nNOS inhibitors abolished these effects. IPostC recovered nNOS activity and arginase expression. IPostC also increased AMP kinase (AMPK) phosphorylation and alleviated oxidative stress, and nNOS and AMPK inhibition abolished these effects. IPostC increased nitrotyrosine production in the cytosol but decreased it in mitochondria. Enhanced phospholamban (PLB) phosphorylation, normalized SR function and decreased Ca(2+) overload were observed following the recovery of nNOS activity, and nNOS inhibition abolished these effects. Similar effects of IPostC were demonstrated in cardiomyocytes in vitro. IPostC decreased oxidative stress partially by regulating uncoupled nNOS and the nNOS/AMPK/peroxisome proliferator-activated receptor gamma coactivator 1 alpha/superoxide dismutase axis, and improved SR function through increasing SR Ca(2+) load. These results suggest that IPostC protected hearts against I/R injury via an nNOS-mediated pathway.
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: M
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D057775:Ischemic Postconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009924:Organ Culture Techniques; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000099211:Phospholamban
chemical_list: D055372:AMP-Activated Protein Kinases; D001119:Arginase; D002118:Calcium; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000099211:Phospholamban; C485290:Ppargc1a protein, mouse; C496321:Nos1 protein, mouse