Abstract 632: Does Cardiac Ang-(1-12) Have A Role In Sex-specific Heart Disease?

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Cardiovascular diseases affect women and men differently and large clinical trials suggest ACE inhibitors may be less effective in women than men receiving treatment for hypertension and heart failure. The discovery that chymase forms Ang II directly from Ang-(1-12) independent of ACE and renin in human hearts, prompted the characterization of sex differences in the cardiac expression of Ang-(1-12) and chymase in the heart of subjects undergoing cardiac surgery. Therefore, the objective of this pilot study is to determine whether the expression and activity of Ang-(1-12) and chymase in the human heart are associated with cardiovascular phenotypes in a sex-specific manner. The portions of left (LA) and right (RA) atrial appendages were obtained from male (LA =13 and RA=9) and female (LA=3 and RA=5) patients undergoing heart surgery. A high affinity purified antibody directed to the COOH-terminus of the full length of human Ang-(1-12) was used to detect immunoreactive Ang-(1-12) in all samples (LA: male=13 and female=3; RA: male=9 and female=5) while control sections were treated with the primary antibody preincubated with 0.115 μM of the Ang-(1-12) peptide to which the antibody was directed. Quantitative analysis was performed with Image J software. Native plasma membranes from LA (males=7 and females=3) and RA (males=7 and females=3) were prepared for chymase activity determination by HPLC. Quantitative analysis of Ang-(1-12) expression revealed significantly higher Ang-(1-12) expression in LA appendages of females (Intensity: 61.41±13.43 units, P=0.04) versus males (29.36±6.07 units) while no sex differences were observed in the RA. Chymase activity also tended to be lower in the LA of females (40.22±9.80 fmol/mg/min) vs. males (57.08±5.48), but values were similar between sexes in the RA. These sex-specific differences in the noncanonical RAS may provide important insight into sex-dependent pathophysiology underlying heart disease in women and in therapeutic decisions in the future.

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