Regulation of Intracellular Signaling During Myocardial Ischemia
Description: Pathophysiological conditions that alter blood flow to the heart trigger aberrant intracellular signaling mechanisms that influence the etiology of disease. The β-adrenergic receptor pathway mediates cAMP-dependent protein kinase A (PKA) signaling in the cardiomyocyte to invoke an inotropic and chronotropic response. In the ischemic myocardium, we have observed that downstream sarcomeric targets of the β-adrenergic receptor — PKA signaling pathway are hypophosphorylated, suggesting that altered blood flow triggers a rapid change in PKA activation dynamics. Current projects in the laboratory are aimed at deciphering the mechanisms governing PKA holoenzyme activation and subunit localization under normal and pathophysiological states, as well as examining countering pathways involving phosphatase and proteasome activation that aim to abrogate the adrenergic signal and restore homeostatic balance.