Adenylyl cyclase increases survival in cardiomyopathy

Background-To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC(VI)) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC(VI). We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC(VI). Methods and Results-Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC(VI) (P<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC(VI), as documented by the ratio of ventricular weight to tibial length (Gq, 11.93 +/- 0.99 mg/mm., n=11; Gq/AC, 8.00 +/- 0.73 mg/mm, n=9; P<0.01) and by left ventricular cardiac myocyte size (Gq, 2800 +/- 254 mum(2), n=4; Gq/AC, 1721 +/- 166 mum(2), n=5; P<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20 +/- 0.15 mm, n=12; Gq/AC, 3.68 +/- 0.12 mm, n=7; P<0.05) and increased fractional shortening (Gq, 32 +/- 1%, n=12; Gq/AC, 41 +/- 2%, n=7; P<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8 +/- 1.3 fmol/cell, n=5; Gq/AC, 10.7 +/- 2.6 fmol/cell, n=6; P<0.02), documenting increased AC function. Conclusions-Cardiac-directed expression of AC(VI) restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.