title: Nitric oxide, PKC-ε, and connexin43 are crucial for ischemic preconditioning-induced chemical gap junction uncoupling.
abstract: Ischemic preconditioning (IPC) maintains connexin43 (Cx43) phosphorylation and reduces chemical gap junction (GJ) coupling in cardiomyocytes to protect against ischemic damage. However, the signal transduction pathways underlying these effects are not fully understood. Here, we investigated whether nitric oxide (NO) and protein kinase C-ε (PKC-ε) contribute to IPC-induced cardioprotection by maintaining Cx43 phosphorylation and inhibiting chemical GJ coupling. IPC reduced ischemia-induced myocardial infarction and increased cardiomyocyte survival; phosphorylated Cx43, eNOS, and PKC-ε levels; and chemical GJ uncoupling. Administration of the NO donor SNAP mimicked the effects of IPC both in vivo and in vitro, maintaining Cx43 phosphorylation, promoting chemical GJ uncoupling, and reducing myocardial infarction. Preincubation with the NO synthase inhibitor L-NAME or PKC-ε translocation inhibitory peptide (PKC-ε-TIP) abolished these effects of IPC. Additionally, by inducing NO production, IPC induced translocation of PKC-ε, but not PKC-δ, from the cytosolic to the membrane fraction in primary cardiac myocytes. IPC-induced cardioprotection thus involves increased NO production, PKC-ε translocation, Cx43 phosphorylation, and chemical GJ uncoupling.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Rong
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xie
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.|School of Medicine, Shandong University, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.|School of Medicine, Shandong University, Jinan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Hao
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.|School of Medicine, Shandong University, Jinan, China.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
chemical_list: D018031:Connexin 43; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D051744:Protein Kinase C-epsilon; D019331:NG-Nitroarginine Methyl Ester
keywords: PKC-ε; Pathology Section; connexin43; gap junction coupling; ischemic preconditioning; nitric oxide