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

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.

• Authors: I-Chen Chen, Jao-Yu Lin, Yi-Ching Liu, Chee-Yin Chai, Jwu-Lai Yeh, Jong-Hau Hsu, Bin-Nan Wu, Zen-Kong Dai
• Journal: International journal of medical sciences (Int J Med Sci) Vol. 17 Issue 16 Pg. 2594-2602 ( 2020) ISSN: 1449-1907 [Electronic] Australia
• PMID: 33029102 (Publication Type: Journal Article)
• Copyright: © The author(s).

Chemical References

• Enzyme Activators
• Peptide Fragments
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• Receptors, G-Protein-Coupled
• Angiotensin II
• Angiotensin I
• Ace2 protein, rat
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)
• diminazene aceturate
• Diminazene

Topics

• Angiotensin I (metabolism)
• Angiotensin II (metabolism)
• Angiotensin-Converting Enzyme 2 (metabolism)
• Animals
• Diminazene (analogs & derivatives, pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Enzyme Activators (pharmacology, therapeutic use)
• Humans
• Hypertension, Pulmonary (drug therapy, etiology)
• Peptide Fragments (metabolism)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins (metabolism)
• Rats
• Rats, Wistar
• Receptors, G-Protein-Coupled (metabolism)
• Renin-Angiotensin System (drug effects)
• Ventricular Dysfunction, Left (complications, drug therapy)