Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR. Issue 4 (4th October 2017)

• Record Type: Journal Article
• Authors: Ahmad, Sarfaraz; Sun, Xuming; Lin, Marina; Varagic, Jasmina; Zapata‐Sudo, Gisele; Ferrario, Carlos M.; Groban, Leanne; Wang, Hao
• Is Part Of: Journal of cellular physiology. Volume 233:Issue 4(2018:Apr.)
• Page Start: 3330
• Page End: 3342
• Publication Date: 2017-10-04
• Subjects: chymase -- diastolic function -- estrogen -- intracrine -- myocyte -- non‐myocyte -- ovariectomy -- paracrine -- renin angiotensin system; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.26179
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract : The relatively low efficacy of ACE‐inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (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 myocytes (CMs) and non‐myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal‐intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/ml vs. SHR: 42 ± 9 pg/ml; p < 0.01), independent of OVX. The enzymatic activities of chymase, ACE, and ACE2 were higher in NCMs versus CMs, irrespective of whether assays were performed in cardiac membranes from WKY or SHR or in the presence or absence of OVX. E2 depletion increased chymase activity, but not ACE activity, in both CMs and NCMs. Moreover, cardiac myocyte chymase activity associated with diastolic function in WKYs and cardiac structure in SHRs while no relevant functional and structural relationships between the classic enzymatic pathway of Ang II formation by ACE or the counter‐regulatory Ang‐(1‐7) forming path from Ang II via ACE2 were apparent. 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. Abstract : Chymase‐mediated angiotensin II formation (or chymase activity) in cardiomyocyte cell membranes is linked to worsening of diastolic function, defined by increased Doppler‐derived filling pressures (E/e′), and increases in left ventricular (LV) mass in normotensive (WKY) and hypertensive (SHR) rats, respectively, after surgically induced menopause.