Adenylyl cyclase 6 deletion reduces left ventricular hypertrophy, dilation, dysfunction, and fibrosis in pressure-overloaded female mice.

ABSTRACT: This study sought to test the hypothesis that pressure stress of the adenylyl cyclase 6-deleted (AC6-KO) heart would result in excessive hypertrophy, early dilation and dysfunction, and increased fibrosis.Cardiac-directed AC6 expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy.AC6-KO and control (CON) mice underwent transverse aortic constriction (TAC) to induce pressure overload. Measures of LV hypertrophy, function, and fibrosis were obtained 3 weeks after TAC, and LV samples were assessed for alterations in expression of FHL1 and periostin.Three weeks after TAC, female AC6-KO mice had preserved left ventricular (LV) ejection fraction (CON: 22+/-2%; AC6-KO: 52+/-4%; p<0.001) and reduced LV end-diastolic dimension (CON: 4.6+/-0.1 mm; AC6-KO: 3.6+/-0.1 mm; p<0.001). Reduced LV/tibial length ratio (CON: 10.4+/-1.5 mg/mm; AC6-KO: 7.5+/-2.3 mg/mm; p<0.001) and reduced LV expression of atrial natriuretic factor (p<0.05), alpha-skeletal muscle actin (p<0.05), and beta-myosin heavy chain (p<0.05) were observed in AC6-KO mice. In addition, AC6 deletion was associated with less LV fibrosis (p<0.01) and reduced collagen types I (p<0.05) and III (p<0.05) expression 3 weeks after TAC. LV protein expression of FHL1 (p<0.02) and periostin (p=0.04) were reduced after TAC in AC6-KO mice. The roles of AC6 deletion in cardiac myocytes and fibroblasts were examined in vitro using pharmacological hypertrophy and AC6 knockdown (small interfering ribonucleic acid), which recapitulated in vivo findings.The deleterious effects of LV pressure overload were reduced in female mice with AC6 deletion. Reductions in FHL1 and periostin expression, direct consequences of reduced AC6 in cardiac myocytes and fibroblasts, appear to be of mechanistic importance for these unanticipated beneficial effects.

SUBMITTER: Tang T 

PROVIDER: S-EPMC3081694 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature