Abstract P283: Effects of Ovarian Estrogens on Local RAS Activity in Cardiomyocytes and Non-cardiomyocytes

Abstract

The relatively low efficacy of ACE-Is in the treatment of heart failure (HF) in women after estrogen (E2) loss may be due to their inability to reach the intracellular sites at which Ang II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated cardiomyocytes (CMs) and non-cardiomyocytes (NCMs) extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Circulating levels of angiotensinogen (AOGEN) were higher in WKY (958 ± 47 pg/mL) vs. SHR (SHR: 626 ± 40 pg/mL; P<0.05 strain effect) and E2 loss augmented this effect in WKY (WKY OVX: 1,169 ± 66 pg/mL vs. SHR OVX: 625 ± 41 pg/mL). Correspondingly, plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/mL vs. SHR: 42 ± 9 pg/mL), independent of OVX. Chymase activity was nearly 40-fold higher in NCMs compared to CMs, and for the NCMs, activities were highest in cells from WKY vs. SHR and OVX vs. intact rats (P<0.05 strain and E2 effects, respectively) (Figure). Neither strain nor gonad status influenced the lower ACE activity found in both NCMs and CMs. In contrast, ACE2 activity in CMs and NCMs was higher in cells from WKY vs. SHR (P<0.05 strain effect), independent of E2 status. We conclude that NCMs from WKY and SHR express significantly higher levels of chymase, ACE, and ACE2 activities. E2 loss leads to selective changes in the activity of chymase, but not ACE, in NCMs. The significance of these novel findings is that targeted cell-specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause.