Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart - Cross-talk between cardiac hypertrophic signaling pathways

Multiple intracellular signaling pathways have been shown to regulate the h ypertrophic growth of cardiomyocytes, Both necessary and sufficient roles h ave been described for the mitogen activated protein kinase (MAPR) signalin g pathway, specific protein kinase C (PKC) isoforms, and calcineurin, Here we investigate the interdependence between calcineurin, MAPK, and PKC isofo rms in regulating cardiomyocyte hypertrophy using three separate approaches . Hearts from hypertrophic calcineurin transgenic mice were characterized f or PKC and MAPK activation. Transgenic hearts demonstrated activation of c- Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ER K1/2), but not p38 MAPK factors. Calcineurin transgenic hearts demonstrated increased activation of PKC alpha, beta(1), and theta, but not of epsilon, beta(2), or lambda. In a second approach, cultured cardiomyocytes were inf ected with a calcineurin adenovirus to induce hypertrophy and the effects o f pharmacologic inhibitors or co-infection with a dominant negative adenovi rus were examined. Calcineurin-mediated hypertrophy was prevented with PKC inhibitors, Ca2+ chelation, and attenuated with a dominant negative SEK-1 ( MKK4) adenovirus, but inhibitors of ERK or p38 activation had no effect. In a third approach, we examined the activation of MAPK factors and PKC isofo rms during the progression of load-induced hypertrophy in aortic banded rat s with or without cyclosporine. We determined that inhibition of calcineuri n activity with cyclosporine prevented PKC alpha, theta, and JNK activation , but did not affect PKC epsilon, beta, lambda, ERK1/2, or p38 activation. Collectively, these data indicate that calcineurin hypertrophic signaling i s interconnected with PKC alpha, theta, and JNK in the heart, while PKC eps ilon, beta, lambda, p38, and ERK1/2 are not involved in calcineurin-mediate d hypertrophy.