When the heart is exposed to potentially harmful stress an important protective response is initiated. In part, this protective response is characterized by sarcomeric stabilization, increased resistance to apoptosis, and the induction of a subset of cardiac genes, some of which contribute to the cardioprotection. The stress response is initially adaptive and can sometimes result in hypertrophic cardiac myocyte growth. Unfortunately, if the stress persists, there is often a cessation of the growth response and, instead, the heart undergoes a remodeling that can be associated with an eventual loss of muscle mass due to increased apoptosis, leading ultimately to heart failure. Our long-term objective is to understand the signal transduction mechanisms responsible for the cardiac myocyte stress response. We recently showed that one of the stress mitogen activated protein kinases, p38 MAPK, plays a central role in this process. This proposal focuses on how p38 contributes to several key features of the cardiac stress response. Our hypothesis is that p38 can induce certain cardiac stress-activated genes through a unique mechanism involving the recently-discovered transcription factor, ATF6. Further, we believe that p38-governed sarcomere stabilization and protection from apoptosis involves the small heat shock proteins (HSPs), alpha B-crystallin (alphaBC) and hsp27, which serve numerous roles, many of which converge on the promotion of cardiac myocyte survival. This hypothesis will be addressed using a cultured cardiac myocyte model system.
Our Specific Aims are: 1) to examine the mechanism by which p38 confers cardiac gene induction through ATF6, 2) to investigate the signal transduction events through which p38 mediates alphaBC and hsp27 gene induction-, phosphorylation- and translocation to sarcomeres, and 3) to assess the effects of manipulating the levels of alphaBC and hsp27 on selected features of the stress response using a novel combined antisense oligonucleotide/overexpression approach. These studies employ novel combinations of molecular approaches to unravel the roles of p38 MAP kinase in the cardiac myocyte stress response. The results will provide new information required to move the field forward in the search for new therapeutic strategies aimed at managing the cardiac stress response.
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