Lack of Gα_i2 leads to dilative cardiomyopathy and increased mortality in β₁-adrenoceptor overexpressing mice

Inhibitory G (G_i) proteins have been proposed to be cardioprotective. We investigated effects of Gα_i2 knockout on cardiac function and survival in a murine heart failure model of cardiac β₁-adrenoceptor overexpression.

β₁-transgenic mice lacking Gα_i2 (β₁-tg/Gα_i2^−/−) were compared with wild-type mice and littermates either overexpressing cardiac β₁-adrenoceptors (β₁-tg) or lacking Gα_i2 (Gα_i2^−/−). At 300 days, mortality of mice only lacking Gα_i2 was already higher compared with wild-type or β₁-tg, but similar to β₁-tg/Gα_i2^−/−, mice. Beyond 300 days, mortality of β₁-tg/Gα_i2^−/− mice was enhanced compared with all other genotypes (mean survival time: 363 ± 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, β₁-tg, and Gα_i2^−/− mice, but significant impairment for β₁-tg/Gα_i2^−/− mice (e.g. ejection fraction 14 ± 2 vs. 40 ± 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 ± 0.06 vs. 0.48 ± 0.02% in wild-type mice), left ventricular size (length 0.82 ± 0.04 vs. 0.66 ± 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. Gα_i3 was significantly up-regulated in Gα_i2 knockout mice (protein compared with wild type: 340 ± 90% in Gα_i2^−/− and 394 ± 80% in β₁-tg/Gα_i2^−/−, respectively).

Gα_i2 deficiency combined with cardiac β₁-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, β₁-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Gα_i2. We propose an enhanced effect of increased β₁-adrenergic drive by the lack of protection via Gα_i2. Gα_i3 up-regulation was not sufficient to compensate for Gα_i2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.