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Aims: Gi-proteins have been proposed to be cardioprotective. We investigated effects of Gαi2-knockout on cardiac function and survival in a murine heart-failure model of cardiac β1-adrenoceptor overexpression. Methods and results: β1-transgenic mice lacking Gαi2 (β1-tg/Gαi2-/-) were compared to wildtypes and littermates either overexpressing cardiac β1-adrenoceptors (β1-tg) or lacking Gαi2 (Gαi2-/-). At 300 days mortality of mice only lacking Gαi2 was already higher compared to wildtype or β1-tg but similar to β1-tg/Gαi2-/- mice. Beyond 300 days mortality of β1-tg/Gαi2-/- mice was enhanced compared to all other genotypes (mean survival time: 363±21 days). At 300 days of age echocardiography revealed similar cardiac function of wildtype, β1-tg and Gαi2-/- mice, but significant impairment for β1-tg/Gαi2-/- mice (e.g. ejection fraction 14±2% versus 40±4% in wildtypes). Significantly increased ventricle- to body-weight ratio (0.71±0.06% versus 0.48±0.02% in wildtypes), left-ventriclular size (length 0.82±0.04 cm versus 0.66±0.03 cm in wildtypes) and ANP and BNP expression (mRNA: 2819% and 495% of wildtype, respectively) indicated hypertrophy. Gαi3 was significantly upregulated in Gαi2-knockouts (protein compared to wildtype: 340±90% in Gαi2-/- and 394±80% in β1-tg/Gαi2-/-, respectively). Conclusions: Gαi2-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 Gαi2. We propose an enhanced effect of increased β1-adrenergic drive by lack of protection via Gαi2. Gαi3 upregulation was not sufficient to compensate for Gαi2 deficency suggesting an isoform-specific or a concentration-dependent mechanism. [ABSTRACT FROM AUTHOR]