| First Author | Keller K | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 108 |
| Issue | 3 | Pages | 348-56 |
| PubMed ID | 26464333 | Mgi Jnum | J:258874 |
| Mgi Id | MGI:6142058 | Doi | 10.1093/cvr/cvv235 |
| Citation | Keller K, et al. (2015) Lack of Galphai2 leads to dilative cardiomyopathy and increased mortality in beta1-adrenoceptor overexpressing mice. Cardiovasc Res 108(3):348-56 |
| abstractText | AIMS: Inhibitory G (Gi) proteins have been proposed to be cardioprotective. We investigated effects of Galphai2 knockout on cardiac function and survival in a murine heart failure model of cardiac beta1-adrenoceptor overexpression. METHODS AND RESULTS: beta1-transgenic mice lacking Galphai2 (beta1-tg/Galphai2 (-/-)) were compared with wild-type mice and littermates either overexpressing cardiac beta1-adrenoceptors (beta1-tg) or lacking Galphai2 (Galphai2 (-/-)). At 300 days, mortality of mice only lacking Galphai2 was already higher compared with wild-type or beta1-tg, but similar to beta1-tg/Galphai2 (-/-), mice. Beyond 300 days, mortality of beta1-tg/Galphai2 (-/-) 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, beta1-tg, and Galphai2 (-/-) mice, but significant impairment for beta1-tg/Galphai2 (-/-) 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. Galphai3 was significantly up-regulated in Galphai2 knockout mice (protein compared with wild type: 340 +/- 90% in Galphai2 (-/-) and 394 +/- 80% in beta1-tg/Galphai2 (-/-), respectively). CONCLUSIONS: Galphai2 deficiency combined with cardiac beta1-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, beta1-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking Galphai2. We propose an enhanced effect of increased beta1-adrenergic drive by the lack of protection via Galphai2. Galphai3 up-regulation was not sufficient to compensate for Galphai2 deficiency, suggesting an isoform-specific or a concentration-dependent mechanism. |
