Work

A human polymorphism of protein phosphatase‐1 inhibitor‐1 is associated with attenuated contractile response of cardiomyocytes to β‐adrenergic stimulation

Year: 2008

Type: article

Abstract: Aberrant β‐adrenergic signaling and de pressed calcium homeostasis, associated with an imbal ance of protein kinase A and phosphatase‐1 activities, are hallmarks of heart failure. Phosphatase‐1 is re strained by its endogenous inhibitor, protein phospha tase inhibitor‐1 (PPI‐1). We assessed 352 normal sub jects, along with 959 patients with heart failure and identified a polymorphism in PPI‐1 (G147D) exclu sively in black subjects. To determine whether the G147D variant could affect cardiac function, we in fected adult cardiomyocytes with adenoviruses expressing D147 or wild‐type (G147) PPI‐1. Under basal con ditions, there were no significant differences in fractional shortening or contraction or relaxation rates. However, the enhancement of contractile parameters after isoproterenol stimulation was significantly blunted in D147 compared with G147 and control myocytes. Similar findings were observed in calcium kinetics. The attenuated β‐agonist response was associ ated with decreased (50%) phosphorylation of phos‐ pholamban (PLN) at serine 16, whereas phosphorylation of troponin I and ryanodine receptor was unaltered. These findings suggest that the human G147D PPI‐1 can attenuate responses of cardiomyo cytes to β‐adrenergic agonists by decreasing PLN phos phorylation and therefore may contribute to deterio rated function in heart failure.— Chen, G., Zhou, X., Nicolaou, P., Rodriguez, P., Song, G., Mitton, B., Pathak, A., Zachariah, A., Fan, G.‐C., Dorn, G. A., II., Kranias, E. G. A human polymorphism of protein phosphatase‐1 inhibitor‐1 is associated with attenuated contractile response of cardiomyocytes to β‐adrenergic stimulation. FASEB J. 22, 1790–1796 (2008)

Source: The FASEB Journal

DOI: 10.1096/fj.07-097428