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Circ Res. 2010 Sep 3;107(5):642-9. doi: 10.1161/CIRCRESAHA.110.217554. Epub 2010 Jul 1.

Activation of PKN mediates survival of cardiac myocytes in the heart during ischemia/reperfusion.

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1
Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Avenue, Newark, NJ 07103, USA.

Abstract

RATIONALE:

The function of PKN, a stress-activated protein kinase, in the heart is poorly understood.

OBJECTIVE:

We investigated the functional role of PKN during myocardial ischemia/reperfusion (I/R).

METHODS AND RESULTS:

PKN is phosphorylated at Thr774 in hearts subjected to ischemia and reperfusion. Myocardial infarction/area at risk (MI/AAR) produced by 45 minutes of ischemia and 24 hours of reperfusion was significantly smaller in transgenic mice with cardiac-specific overexpression of constitutively active (CA) PKN (Tg-CAPKN) than in nontransgenic (NTg) mice (15+/-5 versus 38+/-5%, P<0.01). The number of TUNEL-positive nuclei was significantly lower in Tg-CAPKN (0.3+/-0.2 versus 1.0+/-0.2%, P<0.05). Both MI/AAR (63+/-9 versus 45+/-8%, P<0.05) and the number of TUNEL-positive cells (7.9+/-1.0 versus 1.3+/-0.9%, P<0.05) were greater in transgenic mice with cardiac-specific overexpression of dominant negative PKN (Tg-DNPKN) than in NTg mice. Thr774 phosphorylation of PKN was also observed in response to H(2)O(2) in cultured cardiac myocytes. Stimulation of PKN prevented, whereas inhibition of PKN aggravated, cell death induced by H(2)O(2), suggesting that the cell-protective effect of PKN is cell-autonomous in cardiac myocytes. PKN induced phosphorylation of alpha B crystallin and increased cardiac proteasome activity. The infarct reducing effect in Tg-CAPKN mice was partially inhibited by epoxomicin, a proteasome inhibitor.

CONCLUSIONS:

PKN is activated by I/R and inhibits apoptosis of cardiac myocytes, thereby protecting the heart from I/R injury. PKN mediates phosphorylation of alpha B crystallin and stimulation of proteasome activity, which, in part, mediates the protective effect of PKN in the heart.

PMID:
20595653
PMCID:
PMC3081566
DOI:
10.1161/CIRCRESAHA.110.217554
[Indexed for MEDLINE]
Free PMC Article

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