Abstract 397: DGK zeta Prevents Pressure Overload-induced Cardiac Hypertrophy and Progression to Heart Failure
We have recently reported that diacylglycerol kinase (DGK) zeta prevents cardiomyocyte hypertrophy by regulating the translocation of protein kinase C (PKC) epsilon in vitro. We have also reported that the transgenic (Tg) mice which overexpress DGK zeta protein specifically in cardiomyocytes under the control of alpha-myosin heavy chain (MHC) promoter exhibited suppressed hypertrophic responses induced by G-protein coupled receptor agonists such as angiotensin II and phenylephrine. Here, we subjected DGK zeta Tg mice to pressure overload by transverse aortic constriction (TAC) to investigate whether DGK zeta affects the mechanical stress-induced cardiac hypertrophy and resultant heart failure. Heart weight / body weight ratio 4 weeks after TAC operation was markedly increased in wild type (Wt) mice, but this increase was significantly suppressed in DGK zeta Tg mice. Histological analysis revealed that cross sectional area of cardiomyocytes 4 weeks after TAC operation was significantly increased in Wt mice. However, this increase was abrogated in DGK zeta Tg mice. Wall thickness and end diastric dimension assessed by echocardiography was increased and % fractional shortening was decreased in Wt mice 4 weeks after TAC operation, but these changes were blunted in Tg mice. Next, we performed real-time PCR to determine the gene profiles of TAC hearts. Although fetal gene expressions such as atrial natriuretic factor (ANF) and beta-MHC were increased in Wt mice, Tg mice showed blunted increase, suggesting that DGK zeta overexpression prevented heart failure by inhibiting cardiac hypertrophy. Then, we investigated cardiac fibrosis by Masson’s trichrome staining. Tg mice showed less extent of pressure overload-induced cardiac fibrosis compared with Wt mice, which was consistent with the reduced gene expression levels of collagen I, collagen III and TGF beta-1. PKC alpha, known downstream target of DAG signaling cascade which contribute to the development of cardiac hypertrophy and heart failure, was activated by pressure overload in Wt mice. In contrast, DGK zeta Tg mice showed less activation of PKC alpha. We conclude that DGK zeta plays a pivotal role in preventing pressure overload-induced cardiac hypertrophy and transition to heart failure.