Abstract 320: A Human Polymorphism of Protein Phosphatase 1 Inhibitor 1 is Associated With Attenuated Contractile Responses to Beta-adrenergic Stimulation
Aberrant β-adrenergic signaling associated with depressed calcium homeostasis is one of the most prominent characteristics of heart failure. Abnormalities in protein kinases A as well as protein phosphatase 1 underlie the impaired function of this β-signaling axis. The activity of protein phosphatase 1 is regulated by an endogenous inhibitor, inhibitor-1. In vitro and in vivo studies have indicated that inhibitor-1 is a critical player in the heart’s responses to neurohormonal stimulation. This study identified a novel polymorphism in human inhibitor -1, entailing substitution of aspartic acid for glycine at AA147 (G147D), exclusively in black heart failure patients. To elucidate the functional significance of the G147D inhibitor -1 mutant, we infected adult rat cardiomyocytes with an adenovirus expressing G147D inhibitor -1, wild type inhibitor -1, or control GFP. Under basal conditions, there were no significant differences in fractional shortening, contraction rate or relaxation rate among the three groups. However, the responses of these contractile parameters to isoproterenol stimulation were significantly blunted in cardiomyocytes infected with the G147D variant, compared to the other two groups. Consistent with these mechanical parameters, the velocity of Ca transient decay was significantly delayed. Importantly, phosphorylation of phospholamban at serine 16 was decreased by 50% in G147D-Inhibitor-1 infected cells, although phosphorylation of troponin I and the ryanodine receptor remained unaltered. These findings suggest that the human G147D inhibitor -1 polymorphism attenuates the heart’s responses to β-adrenergic agonists through decreased PLN phosphorylation, which may contribute to compromised heart function and the development of heart failure.