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

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, Deepmala Agarwal, Kamal K. Mubarak, Chastity Bradford, William R. Kennedy, Joo Y. Jun, Anandharajan Rathinasabapathy, Erin Bruce, Dipankar Gupta, Arturo J. Cardounel, J. MoccoJawaharlal M. Patel, Joseph Francis, Maria B. Grant, Michael J. Katovich, Mohan K. Raizada

Research output: Contribution to journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)648-657
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume187
Issue number6
DOIs
StatePublished - Mar 15 2013

Keywords

  • ACE2
  • Angiogenic progenitor cells
  • Diminazen
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Shenoy, V., Gjymishka, A., Jarajapu, Y. P., Qi, Y., Afzal, A., Rigatto, K., Ferreira, A. J., Fraga-Silva, R. A., Kearns, P., Douglas, J. Y., Agarwal, D., Mubarak, K. K., Bradford, C., Kennedy, W. R., Jun, J. Y., Rathinasabapathy, A., Bruce, E., Gupta, D., Cardounel, A. J., ... Raizada, M. K. (2013). Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. American journal of respiratory and critical care medicine, 187(6), 648-657. https://doi.org/10.1164/rccm.201205-0880OC