Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.
BACKGROUND
Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro.


OBJECTIVE
To evaluate the pharmacological actions of DIZE in experimental models of PH.


METHODS
PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH.


RESULTS
DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1α, which was corrected by in vitro DIZE treatment.


CONCLUSIONS
Our results identify a therapeutic potential of DIZE in PH therapy.
Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA.
Vinayak
V
Shenoy
Altin
A
Gjymishka
Yagna P
YP
Jarajapu
Yanfei
Y
Qi
Aqeela
A
Afzal
Katya
K
Rigatto
Anderson J
AJ
Ferreira
Rodrigo A
RA
Fraga-Silva
Patrick
P
Kearns
Jane Yellowlees
JY
Douglas
Deepmala
D
Agarwal
Kamal K
KK
Mubarak
Chastity
C
Bradford
William R
WR
Kennedy
Joo Y
JY
Jun
Anandharajan
A
Rathinasabapathy
Erin
E
Bruce
Dipankar
D
Gupta
Arturo J
AJ
Cardounel
J
J
Mocco
Jawaharlal M
JM
Patel
Joseph
J
Francis
Maria B
MB
Grant
Michael J
MJ
Katovich
Mohan K
MK
Raizada
D000818:Animals; D054443:Cell Migration Assays; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D013234:Stem Cells / Q000502:physiology; D014344:Trypanocidal Agents / Q000494:pharmacology*
D014344:Trypanocidal Agents; C003915:diminazene aceturate; D004133:Diminazene