| First Author | Matsushita N | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 8 | Pages | e106354 |
| PubMed ID | 25171374 | Mgi Jnum | J:219239 |
| Mgi Id | MGI:5619915 | Doi | 10.1371/journal.pone.0106354 |
| Citation | Matsushita N, et al. (2014) Cardiac overexpression of constitutively active Galpha q causes angiotensin II type1 receptor activation, leading to progressive heart failure and ventricular arrhythmias in transgenic mice. PLoS One 9(8):e106354 |
| abstractText | BACKGROUND: Transgenic mice with transient cardiac expression of constitutively active Galpha q (Galphaq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Galphaq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Galphaq-TG mice. METHODOLOGY/PRINCIPAL FINDINGS: Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Galphaq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Galphaq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Galphaq-TG but in none of 10 olmesartan-treated Galphaq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Galphaq-TG than in vehicle-treated Galphaq-TG. CTGF, collagen type 1, ANP, BNP, and beta-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Galphaq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Galphaq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Galphaq-TG. Moreover, it increased AT1 receptor in Galphaq-TG. CONCLUSIONS/SIGNIFICANCE: These findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Galphaq-TG mouse model of heart failure. |
