Differential Expression of Angiotensin-converting Enzyme and Chymase in Dogs with Chronic Mitral Regurgitation

The current study tested the hypothesis that angiotensin-converting enzyme (ACE) and chymase expression are subject to different regulatory processes in the heart, as well as the lungs and kidneys and, as a result, have an important effect on the efficacy of ACE inhibitor treatment in modulating tissue angiotensin II (ANG II) levels in heart failure. A total of 18 dogs underwent the induction of mitral regurgitation and were followed for 5 months. Eleven dogs were untreated and seven received the ACE-inhibitor ramipril at a dose of 10 mg PO BID. Seventeen dogs underwent a sham-operation: six of these dogs were treated with ramipril for 3 months (10 mg PO BID) and 11 were untreated and followed for 3 months prior to sacrifice. In mitral regurgitation dogs, ANG II levels were increased >2-fold in left ventricle, lungs, and kidney, but were normalized with ACE inhibitor-treatment only in the left ventricle. In the left ventricle and lungs steady state ACE mRNA levels and ACE activities were increased 2-fold in treated and untreated mitral regurgitation dogs compared to shams (P<0.05, ANOVA). In contrast, chymase mRNA levels were decreased by >50% and chymase activity was increased in left ventricle (LV) of mitral regurgitation dogs (P<0.05). Neither chymase mRNA nor chymase activity could be detected in the kidney; however, kidney ACE mRNA and ACE activity were significantly upregulated in treated and untreated mitral regurgitation dogs (P<0.05). These results suggest that ACE and chymase expression are regulated differentially in the dog in response to chronic mitral regurgitation and ACE inhibitor treatment. Further, these responses, as well as regulation of ANG II formation, are organ specific.