期刊
ONCOTARGET
卷 7, 期 43, 页码 69243-69255出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12087
关键词
ischemic preconditioning; nitric oxide; PKC-epsilon; connexin43; gap junction coupling; Pathology Section
资金
- Natural Science Foundation of China [81270238]
- Scientific Research Foundation for the Doctoral Degree, State Education Ministry of China [20130131110065]
- Scientific Development Plan of Shandong Province of China [2012G0021850]
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-epsilon (PKC-epsilon) 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-epsilon 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-epsilon translocation inhibitory peptide (PKC-epsilon-TIP) abolished these effects of IPC. Additionally, by inducing NO production, IPC induced translocation of PKC-epsilon, but not PKC-delta, from the cytosolic to the membrane fraction in primary cardiac myocytes. IPC-induced cardioprotection thus involves increased NO production, PKC-epsilon translocation, Cx43 phosphorylation, and chemical GJ uncoupling.
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