• Vinayak Shenoy, Altin Gjymishka, Yagna P Jarajapu, Yanfei Qi, Aqeela Afzal, Katya Rigatto, Anderson J Ferreira, Rodrigo A Fraga-Silva, Patrick Kearns, Jane Yellowlees Douglas, Kamal K Mubarak, Chastity Bradford, William R Kennedy, Joo Y Jun, Anandharajan Rathinasabapathy, Erin Bruce, Arturo J Cardounel, J Mocco, Jawaharlal M Patel, Joseph Francis, Maria B Grant, Michael J Katovich, and Mohan K Raizada.
• Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA.
• Am. J. Respir. Crit. Care Med.. 2013 Mar 15;187(6):648-57.

RationaleStudies 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.ObjectivesTo 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 ResultsDIZE 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.ConclusionsOur results identify a therapeutic potential of DIZE in PH therapy.

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