Perioperative myocardial infarction (MI) remains a significant clinical problem and diabetes is an independent risk factor for both mortality and morbidity after MI. A number of clinical studies have shown that the post-MI left ventricular function is significantly worse in diabetic compared with non- diabetic patients. However, what is lacking is a plausible relationship between diabetes and any of the known regulators of myocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Recently, we have demonstrated that a novel signaling between phosphodiesterase 3A (PDE3A) and inducible cAMP early repressor (ICER), the PDE3A-ICER feedback loop, is a likely mechanism determining the fate of injured myocytes. Our recent preliminary data to be presented in this proposal indicate that ERK5, an atypical mitogen activated protein kinase with transcriptional activity, regulates the PDE3A-ICER feedback loop and that the ERK5 transcriptional activity itself is subjected to down regulation by a hyperglycemia- dependent small ubiquitin-related modification (SUMO). p90RSK, a kinase activated in diabetes, increases ERK5-SUMOylation and inhibits its transcriptional activity. Our working hypothesis is that inhibition of ERK5 transcriptional activity in diabetic heart by p90RSK-mediated ERK5-SUMOylation results in a proapoptotic condition likely to contribute to poor post-MI cardiac ventricular function.
The specific aims are:
Aim 1 : Determine the role of p90RSK activation on streptozotocin-induced exacerbation of left ventricular remodeling after MI, in vivo.
Aim 2. Determine the role of p90RSK-ERK5 axis on streptozotocin- induced exacerbation of LV remodeling after MI in vivo.
Aim 3 : Determine the molecular mechanisms by which p90RSK functions as an inhibitor for ERK5 transcriptional activity in cardiomyocytes, in vitro.
Aim 4 : Determine the role of angiotensin II, reactive oxygen species and high glucose-mediated endogenous p90RSK activation and subsequent ERK5-SUMOylation in PDE3A-ICER feedback loop-mediated apoptosis and inhibition of SERCA2 and 21-adrenergic receptor expression in vitro, and we will investigate the functional significance of the molecular interaction between p90RSK and ERK5 transcriptional regulation through extensive use of adenovirus in an in vitro myocyte ststem. The broad-based experimental approach including the use of various transgenic mice and gene transduction viral vectors should allow us to determine the importance of p90RSK-ERK5 axis in diabetic cardiomyopathy. Moreover, we believe that our novel small molecule specific p90RSK inhibitor should provide a new therapeutic strategy for reducing post- ischemic cardiac dysfunction in diabetics. ? ? ?
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