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

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

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 H₂O₂ in cultured cardiac myocytes. Stimulation of PKN prevented, whereas inhibition of PKN aggravated, cell death induced by H₂O₂, suggesting that the cell-protective effect of PKN is cell-autonomous in cardiac myocytes. PKN induced phosphorylation of α B crystallin and increased cardiac proteasome activity. The infarct reducing effect in Tg-CAPKN mice was partially inhibited by epoxomicin, a proteasome inhibitor.

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