Abstract 540: Effects Of Altered Levels Of Adenylyl Cyclase Type 5 In Cardiac Myocytes From Chimeric Mice
The role of adenylyl cyclase (AC) isoforms in the heart has remained controversial in regards to their ability to enhance or impair cardiac function. We examined the effects of chronic pressure overload (aortic banding) in transgenic (TG) mice with cardiac overexpressed AC isoform type 5 (AC5TG), a major cardiac AC isoform. In AC5TG, the hypertrophic response, as assessed by LV/tibia length (TL), was greater, p<0.05, in AC5TG (6.6±0.2) than wildtype (WT) (5.1±0.2). In addition, cardiac decompensation occurred, as reflected by decreased LV ejection fraction and increased lung/body weight, which could exert systemic effects through reflexes and hormones. We sought to examine whether the effects of overexpressed AC5 on the response to pressure overload is due to the affects on the myocyte or its environment. Chimeric mice from fusion between embryos from the transgenic overexpressed AC5 parents and the Rosa26 parents, which ubiquitously express beta-galactosidase in all tissues and can be identified histologically with X-gal staining, were developed. The proportion of the AC5TG (FVB background) cells in the myocardium ranged from 2% to 75% (n=9). We subjected these animals to 2 wk aortic banding at 4 – 6 months of age and examined the physiological and histological changes in the heart. There was a direct correlation (r= 0.91) between the percentage of AC5OE cells and LV hypertrophy index (LV weight/BW) including LV end diastolic and systolic wall thickness (r=0.98 and 0.92, respectively). We then determined the myocyte cross-sectional cell size from different cell origin micrographically. After 2wk banding, myocytes originating from the Rosa26 (C57/BL6) and FVB background were similar in size, but myocytes overexpressing AC5 were significantly larger (33%, p<0.05). Conversely, there was a negative correlation between the amount of AC5OE cells and heart function: LV ejection fraction and contractility decreased in mice with a higher percentage of AC5OE myocytes (r = −0.89 and r = −0.81, respectively). Thus, overexpression of AC5 even in only a small fraction of total myocytes in the heart induced myocyte hypertrophy independent of any systemic influences.