Int J Med Sci 2020; 17(16):2594-2602. doi:10.7150/ijms.48096

Research Paper

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction

I-Chen Chen1,2,3, Jao-Yu Lin4, Yi-Ching Liu1, Chee-Yin Chai5, Jwu-Lai Yeh3,6, Jong-Hau Hsu1,2, Bin-Nan Wu3,6✉, Zen-Kong Dai1,2,3✉

1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
2. Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
3. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4. Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
5. Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
6. Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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Citation:
Chen IC, Lin JY, Liu YC, Chai CY, Yeh JL, Hsu JH, Wu BN, Dai ZK. The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction. Int J Med Sci 2020; 17(16):2594-2602. doi:10.7150/ijms.48096. Available from http://www.medsci.org/v17p2594.htm

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Abstract

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

Keywords: pulmonary hypertension, left ventricular dysfunction, renin-angiotensin system, ACE2 activator, ACE2-Ang-(1-7)-MAS axis