Gαl _i2 signaling: Friend or foe in cardiac injury and heart failure?

Receptors coupled to G proteins have many effects on the heart. Enhanced signaling by Gα _s and Gα _q leads to cardiac injury and heart failure, while Gα _i2 signaling in cardiac myocytes can protect against ischemic injury and β- adrenergic-induced heart failure. We asked whether enhanced Gα _i2 signaling in mice could protect against heart failure using a point mutation in Gα _i2 (G184S), which prevents negative regulation by regulators of G protein signaling. Contrary to our expectation, it worsened effects of a genetic dilated cardiomyopathy (DCM) and catecholamineinduced cardiac injury. Gα _i2 G184S/+/DCM double heterozygote mice (TG9+Gα _i2 G184S/+) had substantially decreased survival compared to DCM animals. Furthermore, heart weight/body weight ratios (HW/BW) were significantly greater in TG9+Gα _i2 G184S/+ mice as was expression of natriuretic peptide genes. Catecholamine injury in Gα _i2 G184S/G184S mutant mice produced markedly increased isoproterenolinduced fibrosis and collagen III gene expression vs WT mice. Cardiac fibroblasts from Gα _i2 ^G184S/G184S mice also showed a serum-dependent increase in proliferation and ERK phosphorylation, which were blocked by pertussis toxin and a mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Gα _i2 signaling in cardiac myocytes protects against ischemic injury but enhancing Gα _i2 signaling overall may have detrimental effects in heart failure, perhaps through actions on cardiac fibroblasts.