Cardiac Overexpression of Constitutively Active Galpha q Causes Angiotensin II Type1 Receptor Activation, Leading to Progressive Heart Failure and Ventricular Arrhythmias in Transgenic Mice

BACKGROUND: Transgenic mice with transient cardiac expression of constitutively active Galpha q (Gα(q)-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gα(q) becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gα(q)-TG mice. METHODOLOGY/PRINCIPAL FINDINGS: Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Gα(q)-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 Gα(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gα(q)-TG but in none of 10 olmesartan-treated Gα(q)-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gα(q)-TG than in vehicle-treated Gα(q)-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gα(q)-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 (AT(1)) receptor was increased in Gα(q)-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gα(q)-TG. Moreover, it increased AT(1) receptor in Gα(q)-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 Gα(q)-TG mouse model of heart failure.