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.