Targeting myocardial β-adrenergic receptor signaling and calcium cycling for heart failure gene therapy

Heart failure (HF) is a leading cause of morbidity and mortality in Western countries and projections reveal that HF incidence in the coming years will rise significantly because of an aging population. Pharmacologic therapy has considerably improved HF treatment during the last 2 decades, but fails to rescue failing myocardium and to increase global cardiac function. Therefore, novel therapeutic approaches to target the underlying molecular defects of ventricular dysfunction and to increase the outcome of patients in HF are needed. Failing myocardium generally exhibits distinct changes in P-adrenergic receptor (PAR) signaling and intracellular Ca2+-handling providing opportunities for research. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies to alter myocardial function and to target both PAR signaling and Ca2+-cycling. In this review, we will discuss functional alterations of the PAR system and Ca2+-handling in HF as well as corresponding therapeutic strategies. We will then focus on recent in vivo gene therapy strategies using the targeted inhibition of the PAR kinase (beta ARK1 or GRK2) and the restoration of S100AI protein expression to support the injured heart and to reverse or prevent HF.