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 catecholamine-induced 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 isoproterenol-induced 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.