Angiotensin-converting enzyme 2 activator ameliorates severe pulmonary
hypertension in a rat model of left pneumonectomy combined with VEGF
inhibition
Abstract
Background Pulmonary artery 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
(25mg/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/group): (1) sham-operated group, (2)
vehicle-treatment group (SuPNx42), (3) early treatment group
(SuPNx42/DIZE1-42) with DIZE at 15 mg/kg/day, subcutaneously from day 1
to day 42, and (4) late treatment group (SuPNx42/DIZE29-42) with DIZE
from day 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.