Exercise training normalizes ACE and ACE2 in the brain of rabbits with pacing induced chronic heart failure

Abstract

Activation of the brain renin‐angiotensin system (RAS) and elevated Angiotensin II (Ang II) increase sympathetic nerve activity (SNA) in chronic heart failure (CHF). Exercise training (EX) normalizes SNA and plasma Ang II. The mechanisms are unclear, but EX may modulate components of the RAS such as Angiotensin‐converting enzyme (ACE) and ACE2. This study investigated the effect of EX on the regulation of ACE and ACE2 in the brain with a pacing CHF+EX model. We hypothesized that the ratio of ACE to ACE2 would increase in CHF to mediate increased SNA and be normalized by EX. Experiments were performed on four groups of rabbits: normal, normal+EX, CHF, and CHF+EX (n=4‐5/group). We analyzed the cortex, cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM by Western blotting, PCR, and double immunofluorescence (IF). ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF (0.3±0.03 to 0.8±0.1, RVLM, P<0.05). EX normalized this in all areas (0.8±0.1 to 0.4±0.1, RVLM). ACE2 protein and mRNA significantly decreased in CHF and also normalized with EX. IF showed ACE2 is present in the cytoplasm of neurons and ACE in endothelial cells. This suggests RAS activation involves an imbalance of ACE and ACE2 and may mediate changes in Ang II and Ang 1‐7 in regions of the brain that regulate autonomic function and suggests EX as a therapy to normalize SNA in CHF.