Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models

Authors

Vinayak Shenoy, University of Florida
Altin Gjymishka, University of Florida
Yagna P. Jarajapu, University of Florida
Yanfei Qi, University of Florida
Aqeela Afzal, University of Florida
Katya Rigatto, University of Florida
Anderson J. Ferreira, Universidade Federal de Minas Gerais
Rodrigo A. Fraga-Silva, Universidade Federal de Minas Gerais
Patrick Kearns, University of Florida
Jane Yellowlees Douglas, University of Florida
Deepmala Agarwal, Louisiana State University
Kamal K. Mubarak, University of Florida
Chastity Bradford, University of Florida
William R. Kennedy, University of Florida
Joo Y. Jun, University of Florida
Anandharajan Rathinasabapathy, University of Florida
Erin Bruce, University of Florida
Dipankar Gupta, University of Florida
Arturo J. Cardounel, The Ohio State University
J. Mocco, University of Florida
Jawaharlal M. Patel, University of Florida
Joseph Francis, Louisiana State University
Maria B. Grant, University of Florida
Michael J. Katovich, University of Florida
Mohan K. Raizada, University of Florida

Document Type

Article

Abstract

Rationale : 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. Objectives: 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. Measurements and Main 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. Copyright © 2013 by the American Thoracic Society.

Publication Date

3-15-2013

Publication Title

American Journal of Respiratory and Critical Care Medicine

ISSN

1073449X

E-ISSN

15354970

Volume

187

Issue

6

First Page

648

Last Page

657

PubMed ID

23370913

Digital Object Identifier (DOI)

10.1164/rccm.201205-0880OC

Recommended Citation

Shenoy, Vinayak; Gjymishka, Altin; Jarajapu, Yagna P.; Qi, Yanfei; Afzal, Aqeela; Rigatto, Katya; Ferreira, Anderson J.; Fraga-Silva, Rodrigo A.; Kearns, Patrick; Douglas, Jane Yellowlees; Agarwal, Deepmala; Mubarak, Kamal K.; Bradford, Chastity; Kennedy, William R.; Jun, Joo Y.; Rathinasabapathy, Anandharajan; Bruce, Erin; Gupta, Dipankar; Cardounel, Arturo J.; Mocco, J.; Patel, Jawaharlal M.; Francis, Joseph; Grant, Maria B.; Katovich, Michael J.; and Raizada, Mohan K., "Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models" (2013). Radiation Oncology. 2.
https://scholar.barrowneuro.org/radiation-oncology/2