Abstract 1835: Absence of LV Dilation, Reduced LV Hypertrophy and Relative Preservation of LV Function after Transverse Aortic Constriction in Mice with Adenylyl Cyclase 6 Deletion
Background: Left ventricular hypertrophy (LVH) is an expected response to pressure overload induced by transverse aortic constriction (TAC), but ultimately LV dilation and failure occur in this model. In this study, we determined the role of adenylyl cyclase 6 (AC6), in LV remodeling and function 3w after TAC, using a newly generated line of AC6-deleted mice (AC6KO).
Methods & Results: Female AC6KO and intact sibling control (CON) mice underwent TAC. LV size (end-diastolic diameter, EDD) and function (fractional shortening, FS) were assessed by echocardiography 1 and 3w later. HR during echocardiography averaged 507 bpm (p=0.98) and mortality at 3w was similar (p=0.75). CON mice showed progressive LV dilation and LV dysfunction (Table⇓), as expected in this model. In contrast, AC6KO mice showed no LV dilation and a reduced decrement in LV function (Table⇓). For example, although there was a 47% decline in LV function from 1w to 3w in control mice (p<0.001), LV function did not decline in this interval in AC6KO mice. LVH was reduced in AC6KO (LVW/tibial length (TL) - CON: 10.4±1.5 mg/mm, n=7; AC6KO: 7.5±2.3 mg/mm, n=13; p=0.008); normal LVW/TL (pre-TAC) is 6.5 mg/mm and unaffected by AC6 deletion. These changes in response to TAC were accompanied, in AC6KO mice, by 38–52% reductions in LV expression of ANF (p=0.01), β-MHC (p=0.01) and α-skeletal muscle actin (p=0.009). LV histone deacetylase 5 (HDAC5) phosphorylation (promotes LVH) and expression of periostin (a regulator of LV remodeling) both were diminished by AC6 deletion (HDAC5-P: −35%, p=0.02; periostin: −47%, p=0.01).
Conclusion: Attenuation of LVH, absence of LV dilation, and relative preservation of LV function were seen after TAC in mice with AC6 deletion. Signaling pathways linking AC6 deletion with these consequences and the roles of HDAC5, periostin, and other proteins influencing the hypertrophic response to pressure overload (MEF2, NFAT, GATA4, GSK3β, JNK, p38, ERK1/2) are a current focus of our laboratory.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).