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The Level of Cardiac Specific Overexpression of Adenylyl Cyclase Type 2 Dictates the Response to Chronic Pressure Overload

The major adenylyl cyclase (AC) isoforms in the heart are AC5 and AC6, which when overexpressed, exert different effects on the response to chronic pressure overload (CPO). Accordingly, the goal of this study was to examine the effects of overexpression (OE) of an AC isoform, which does not normally play a major role in the heart, eg, AC2, on the response to CPO. Two lines were generated: one with moderate AC2 OE of the transgene and the other with a higher level. The AC2 protein was 2 times greater in the line with higher OE. At least 6 WT and 6 AC2 OE from each group were subjected to transverse aortic constriction (TAC) or sham (S) operation for 1 week. With moderate AC2 OE, CPO did not affect the LV ejection fraction (EF) measured with echocardiography (75±1%) vs WT banded (72±1%), or with sham operated animals (76±1%). With higher AC2 OE, 1 week of CPO leads to a significant decrease in LVEF compared with WT (47±4 vs 72±1%) and increase in LVEDP (22.1±7.8 vs 3.5±0.5 mmHg). These were associated with more LV hypertrophy [LV weight/body weight (BW) ratio increased 121% vs 31%] and development of heart failure, as reflected by increased lung weight/BW (278%) vs WT (11%), and 3‐fold more fibrosis on histopathological examination. Thus, cardiac expression of AC2 at a moderate level does not affect the response to CPO adversely, but at a high level, results in more LV hypertrophy and reduced cardiac function leading to heart failure.