Introduction
Pulmonary hypertension (PH) is a progressive and presently incurable
disorder, which complicates the majority of cardiovascular and
respiratory diseases.1,2 The etiology of PH is
classified by WHO into the following five distinct groups: (1) pulmonary
artery hypertension (PAH), (2) PH due to left heart disease, (3) PH due
to lung disease and/or hypoxia, (4) chronic thromboembolic pulmonary
hypertension, and (5) unclear multifocal mechanisms.3All of these groups share a mean, resting, pulmonary arterial pressure
(PAP) of greater than 20 mmHg.4 The pathogenesis of PH
is complexed and multifactorial; proliferative vasculopathy, pulmonary
vascular remodeling, vascular constriction, and endothelial cell
dysfunction have been proven in several previous
studies.5,6
As rodent models are beneficial for understanding the pathophysiology
of PH and for testing experimental therapies, more and more rodent
models have been developed and many of them have exhibited
characteristics mimicking WHO’s classification of human
PH.6 Traditionally, rat models of pulmonary artery
hypertension (PAH) include monocrotaline (with or without pneumonectomy
and/or hypoxia), chronic hypoxia together with SU5416
(3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one; a VEGF
(Vascular endothelial growth factor) receptor-2 inhibitor, and the
fawn-hooded rat (FHR).7-9 A major advantage of the
SU5416 hypoxia models over that of the monocrotaline hypoxia one is the
remodeling of neointimal occlusive lesion, which accumulates unique
tumorlets of endothelial cells and obliterates medium-sized precapillary
arteries. It has also been shown that the SU5416 hypoxia model developed
pulmonary arterial changes resembling plexiform-like lesions, which are
characteristic features of human PAH, by increasing apoptosis of
endothelial cells followed by converting them into apoptosis resistant
and phenotypically altered endothelial cells.10Recently, a newly developed rodent PAH model that combined left
pneumonectomy with SU5416 was reported.11 Unlike the
traditional SU5416 hypoxia model in which a partial reversal of PAH is
seen upon returning to normoxia, this new animal model does not reverse
hypoxia-induced vasoconstriction and hemoconcentration under similar
conditions. Rather, the right ventricular systolic pressure increased
gradually over time, a feature that may favor the assessment of drug
effects in preclinical trials.11
The Renin-angiotensin system (RAS) has been implicated in playing a
causative role in PH.12,13 There are two opposing arms
in RAS: the presser arm, composed of angiotensin converting enzyme
(ACE), angiotensin II (Ang II) produced from Ang I by ACE, and the Ang
II type 1 (AT1) receptor as the main protein mediating the biological
actions of Ang II; and the vasodilator arm, consisting angiotensin
converting enzyme 2 (ACE2), Ang-(1-7) generated through hydrolysis of
Ang II by ACE2, and the Mas receptor as the protein conveying the
vasodilatory, antiproliferative, antifibrotic, and antithrombotic
effects of Ang-(1-7).12,13,14 Therefore, an increase
in the levels of Ang-(1-7) should have beneficial effects for PAH.
However, targeting the ACE2/Ang (1-7)/Mas receptor pathway in PAH is
still under scrutiny.
ACE2 has exhibited its modulating ability in the balance between
vasoconstriction and vasodilation in many
experiments.15,16 Recently, diminazene aceturate
(DIZE), a Food and Drug Administration (FDA) approved anti-trypanosomal
drug, has been demonstrated to exert off-target effect on activating
ACE2.17,18 This effect of DIZE has been confirmed
through the analysis of cleavage of the vasoconstrictor peptide Ang II,
the most physiologically relevant natural substrate for
ACE2.17
On the basis of the benefits demonstrated by DIZE in other PH
models,18-20 we aimed to evaluate its effects on a rat
model of PAH induced by left pneumonectomy combined with SU5416. We
reasoned that in this model there could be an up-regulated expression of
ACE, leading to the imbalance between vasoconstriction and vasodilation.
Treatment with DIZE would increase the levels of ACE2, and hence, the
vasodilatory peptide Ang-(1-7) to prevent and ameliorate the development
of PAH.