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Circulation Research. 2005;96:748-755
Published online before print March 10, 2005, doi: 10.1161/01.RES.0000161999.86198.1e
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(Circulation Research. 2005;96:748.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Increased Collagen Deposition and Diastolic Dysfunction but Preserved Myocardial Hypertrophy After Pressure Overload in Mice Lacking PKC{epsilon}

Gunnar Klein*, Arnd Schaefer*, Denise Hilfiker-Kleiner, Dagmar Oppermann, Praphulla Shukla, Anja Quint, Eva Podewski, Andres Hilfiker, Frank Schröder, Michael Leitges, Helmut Drexler

From the Department of Cardiovascular Medicine (G.K., A.S., D.H.-K., D.O., P.S., A.Q., E.P., A.H., F.S., H.D.), Hannover Medical School, Germany; and the Department of Experimental Endocrinology (M.L.), Max-Planck-Institute, Hannover, Germany.

Correspondence to Gunnar Klein, MD, Abt Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str 1, 30625 Hannover, Germany. E-mail gunnarklein{at}yahoo.de

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}, PKCß, 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.


Key Words: hypertrophy • protein kinase C • mitogen-activated protein kinases


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