Targeting Protein Phosphatase 1 in Heart Failure

ver the past three decades the treatment of heart failure has shifted from a palliative care approach to a more successful focus on neurohormonal modulation through drugs that inhibit ␤-adrenergic, angiotensin, and aldosterone signaling.Despite these relatively recent advances, the clinical syndrome of heart failure remains progressive in nature.This observation begs the question as to a unifying aberrancy in cardiomyocyte phenotype that occurs in heart failure.2][3][4] This slower decline has been attributed to a decrease in the Ca 2ϩ uptake into the sarcoplasmic reticulum (SR); and particularly with the relative role of phospholamban (PLB) and the SR Ca 2ϩ -ATPase (SERCA). 4,5][4][5][6] In this issue, Pathak and del Monte et al show that targeted inhibition of protein phosphatase 1 (PP1) by increased activity of its inhibitor, inhibitor-1 in the heart, results in enhanced contractility and is protective against the development of cardiac hypertrophy and heart failure stimulated by hemodynamic load. 7In failing hearts, the downregulation of adrenergic receptor and cAMP-dependent protein kinase signaling leads to the inactivation of inhibitor-1 which, in turn, results in increased activity of PP1. 7,8This activation of PP1 leads to the dephosphorylation of phospholamban thus reducing calcium uptake by SERCA-2a.In an important series of experiments in transgenic mice and using gene transfer in rats, Kranias, Hajjar, and colleagues now show that the targeted inhibition of protein phosphatase 1 by overexpression of inhibitor-1 enhances cardiac contractility under normal hemodynamic conditions as well as in response to adrenergic stimulation with isoproterenol.Moreover, the authors show that targeted gene transfer of active inhibitor-1 in rats results in marked attenuation of the functional and morphometric changes associated with chronic pressure overload.