A major research interest in my laboratory is focused on protein kinase signaling in hypertrophying myocardium:

(i) Protein kinase signaling in hypertrophying myocardium:

      Hypertrophy is the basic adaptive response of the adult heart to hemodynamic overload such as pressure or volume overload. While the initial response to the increased demand of cardiac muscle function is compensated by the hypertrophic growth of the cardiac muscle cell, this functionality fails and results in congestive heart failure (CHF) when the load increase exceeds the growth capacity. Therefore, it is important to identify the intermediate pathways both during the initial compensatory hypertrophy and during the transition into decompensatory hypertrophy resulting in CHF. Our recent experiments in the initial phase of pressure overload-induced cardiac hypertrophy showed the presence of two major signaling pathways:

      (a) During an early period of pressure overload (1 to 4 hr), a signaling cascade that is independent of integrins, occurs with the activation of protein kinase C, c-Raf and p70/85S6K (S6K1). Since S6K1 is important for enhancing the translational capacity of the cell, we are studying the mechanism and role of PKC/c-Raf/MEK/ERK pathway in the activation of S6K1 and in the mobilization of ribosomal mRNA possessing polypyrimidine tract in the 5'-untranslated region (5'-TOP mRNA) into polysomes for protein translation.

     (b) During the later period of pressure overload (4 to 48 hr), an integrin-dependent signaling occurs that results in the cytoskeletal (CSK) assembly and activation of non-receptor tyrosine kinases (focal adhesion kinase (FAK and c-Src) and several adapter proteins (p130Cas, Nck and Shc). To determine the role of this assembly, we have developed a cell culture model in which integrin is activated with Arg-Gly-Asp (RGD) peptide after embedding adult cardiocytes in collagen gel. This model mimics most of our in vivo data on integrin activation and focal complex formation. We are exploring the importance of this activation with respect to hypertrophic growth (possibly for the sustained activation of S6K1) and survival of adult cardiocytes (by the activation of NFkB and STAT3 signaling pathways).