Increased collagen deposition and Diastolic dysfunction but preserved myocardial hypertrophy after pressure overload in mice lacking PKCε

Overexpression and activation of protein kinase C-epsilon (PKC epsilon) results in myocardial hypertrophy. However, these observations do not establish that PKC epsilon is required for the development of myocardial hypertrophy. Thus, we subjected PKC epsilon-knockout (KO) mice to a hypertrophic stimulus by transverse aortic constriction (TAC). KO mice show normal cardiac morphology and function. TAC caused similar cardiac hypertrophy in KO and wild-type (WT) mice. However, KO mice developed more interstitial fibrosis and showed enhanced expression of collagen I alpha 1 and collagen III after TAC associated with diastolic dysfunction, as assessed by tissue Doppler echocardiography (Ea/Aa after TAC: WT 2.1 +/- 0.3 versus KO 1.0 +/- 0.2; P < 0.05). To explore underlying mechanisms, we analyzed the left ventricular (LV) expression pattern of additional PKC isoforms (ie, PKC alpha, PKC beta, and PKC delta). After TAC, expression and activation of PKC delta protein was increased in KO LVs. Moreover, KO LVs displayed enhanced activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), whereas p42/p44-MAPK activation was attenuated. Under stretch, cultured KO fibroblasts showed a 2-fold increased collagen I alpha 1 (col I alpha 1) expression, which was prevented by PKC delta inhibitor rottlerin or by p38 MAPK inhibitor SB 203580. In conclusion, PKC epsilon is not required for the development of a pressure overload-induced myocardial hypertrophy. Lack of PKC epsilon results in upregulation of PKC delta and promotes activation of p38 MAPK and JNK, which appears to compensate for cardiac hypertrophy, but in turn, is associated with increased collagen deposition and impaired diastolic function.