期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 234, 期 9, 页码 15048-15060出版社
WILEY
DOI: 10.1002/jcp.28146
关键词
hypoxia-reoxygenation; ischemic cardiomyopathy; mitochondrial oxidants; oxidative injury; voltage-independent Ca2+ channels
资金
- National Heart, Lung, and Blood Institute [PO1-HL91799, RO1-HL86699, RO1-HL093671, RO1-HL122124, RO1-HL137266, RO1-HL137426, RO1HL123093]
- National Institute of General Medical Sciences [R01-GM117014]
- National Institute of Neurological Disorders and Stroke [UO1-NS097162, R21-NS098991]
- National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK46778]
The mechanisms by which Trpm2 channels enhance mitochondrial bioenergetics and protect against oxidative stress-induced cardiac injury remain unclear. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in Trpm2 signaling is explored. Activation of Trpm2 in adult myocytes with H2O2 resulted in 10- to 21-fold increases in Pyk2 phosphorylation in wild-type (WT) myocytes which was significantly lower (40%) in Trpm2 knockout (KO) myocytes. Pyk2 phosphorylation was inhibited (54%) by the Trpm2 blocker clotrimazole. Buffering Trpm2-mediated Ca2+ increase with 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid (BAPTA) resulted in significantly reduced pPyk2 in WT but not in KO myocytes, indicating Ca2+ influx through activated Trpm2 channels phosphorylated Pyk2. Part of phosphorylated Pyk2 translocated from cytosol to mitochondria which has been previously shown to augment mitochondrial Ca2+ uptake and enhance adenosine triphosphate generation. Although Trpm2-mediated Ca2+ influx phosphorylated Ca2+-calmodulin kinase II (CaMKII), the CaMKII inhibitor KN93 did not significantly affect Pyk2 phosphorylation in H2O2-treated WT myocytes. After ischemia/reperfusion (I/R), Pyk2 phosphorylation and its downstream prosurvival signaling molecules (pERK1/2 and pAkt) were significantly lower in KO-I/R when compared with WT-I/R hearts. After hypoxia/reoxygenation, mitochondrial membrane potential was lower and superoxide level was higher in KO myocytes, and were restored to WT values by the mitochondria-targeted superoxide scavenger MitoTempo. Our results suggested that Ca2+ influx via tonically activated Trpm2 phosphorylated Pyk2, part of which translocated to mitochondria, resulting in better mitochondrial bioenergetics to maintain cardiac health. After I/R, Pyk2 activated prosurvival signaling molecules and prevented excessive increases in reactive oxygen species, thereby affording protection from I/R injury.
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