Angiotensin-Converting Enzyme 2 Activator Ameliorates Severe Pulmonary Hypertension in a Rat Model of Left Pneumonectomy Combined With VEGF Inhibition

Frontiers in Medicine

article

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

[1] Department of Pediatrics, Kaohsiung Medical University Hospital;Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University;College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University;Department of Surgery, Kaohsiung Medical University;Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University;Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University

关键词: pulmonary arterial hypertension;    left pneumonectomy;    SU5416;    ACE2 activator;    diminazene aceturate;    ACE2-Ang (1-7)-Mas axis;   

DOI  :  10.3389/fmed.2021.619133

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Background: Pulmonary arterial hypertension (PAH) is a life-threatening and deteriorating disease with no promising therapy available currently due to its diversity and complexity. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism of PAH. Angiotensin-converting enzyme 2 (ACE2), which catalyzes the hydrolysis of the vasoconstrictor angiotensin (Ang) II into the vasodilator Ang-(1-7), has been shown to be an important regulator of blood pressure and cardiovascular diseases. Herein we hypothesized diminazene aceturate (DIZE), an ACE2 activator, could ameliorate the development of PAH and pulmonary vascular remodeling. Methods: A murine model of PAH was established using left pneumonectomy (PNx) on day 0 followed by injection of a single dose of the VEGF receptor-2 inhibitor SU5416 (25 mg/kg) subcutaneously on day 1. All hemodynamic and biochemical measurements were done at the end of the study on day 42. Animals were divided into 4 groups ( n = 6–8/group): (1) sham-operated group, (2) vehicle-treatment group (SuPNx 42 ), (3) early treatment group (SuPNx 42 /DIZE 1−42 ) with DIZE at 15 mg/kg/day, subcutaneously from day 1 to day 42, and (4) late treatment group (SuPNx 42 /DIZE 29−42 ) with DIZE from days 29–42. Results: In both the early and late treatment groups, DIZE significantly attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, and right ventricle brain natriuretic peptide ( BNP), as well as reversed the overexpression of ACE while up-regulating the expression of Ang-(1-7) when compared with the vehicle-treatment group. In addition, the early treatment group also significantly decreased plasma BNP and increased the expression of eNOS. Conclusions: ACE2 activator has therapeutic potentials for preventing and attenuating the development of PAH in an animal model of left pneumonectomy combined with VEGF inhibition. Activation of ACE2 may thus be a useful therapeutic strategy for the treatment of human PAH.

【 授权许可】

CC BY