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


BACKGROUND
Cardiac-directed AC6 expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tang
Tong
T
VA San Diego Healthcare System, Department of Medicine, University of California San Diego, San Diego, California 92161, USA. ttang@vapop.ucsd.edu
Lai
N Chin
NC
Hammond
H Kirk
HK
Roth
David M
DM
Yang
Yuan
Y
Guo
Tracy
T
Gao
Mei Hua
MH
D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics; D017384:Sequence Deletion; D018487:Ventricular Dysfunction, Left / Q000235:genetics*
D015815:Cell Adhesion Molecules; C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C082838:Postn protein, mouse; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6