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

60 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Diminazene
Pulmonary Hypertension
Theoretical Models
Stem Cells
Monocrotaline
Therapeutics
Bone Marrow
diminazene aceturate
Lung
Chemotactic Factors
Bleomycin
Renin-Angiotensin System
Angiotensin-Converting Enzyme Inhibitors
Pharmaceutical Preparations
Lung Diseases
Sprague Dawley Rats
Disease Progression

Keywords

  • ACE2
  • Angiogenic progenitor cells
  • Diminazen
  • Pulmonary hypertension

ASJC Scopus subject areas

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

Cite this

Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. / 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.; Raizada, Mohan K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 187, No. 6, 15.03.2013, p. 648-657.

Research output: Contribution to journalArticle

Shenoy, V, Gjymishka, A, Jarajapu, YP, Qi, Y, Afzal, A, Rigatto, K, Ferreira, AJ, Fraga-Silva, RA, Kearns, P, Douglas, JY, Agarwal, D, Mubarak, KK, Bradford, C, Kennedy, WR, Jun, JY, Rathinasabapathy, A, Bruce, E, Gupta, D, Cardounel, AJ, Mocco, J, Patel, JM, Francis, J, Grant, MB, Katovich, MJ & Raizada, MK 2013, 'Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models', American Journal of Respiratory and Critical Care Medicine, vol. 187, no. 6, pp. 648-657. https://doi.org/10.1164/rccm.201205-0880OC
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. ; Raizada, Mohan K. / Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. In: American Journal of Respiratory and Critical Care Medicine. 2013 ; Vol. 187, No. 6. pp. 648-657.
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AU - Shenoy, Vinayak

AU - Gjymishka, Altin

AU - Jarajapu, Yagna P.

AU - Qi, Yanfei

AU - Afzal, Aqeela

AU - Rigatto, Katya

AU - Ferreira, Anderson J.

AU - Fraga-Silva, Rodrigo A.

AU - Kearns, Patrick

AU - Douglas, Jane Yellowlees

AU - Agarwal, Deepmala

AU - Mubarak, Kamal K.

AU - Bradford, Chastity

AU - Kennedy, William R.

AU - Jun, Joo Y.

AU - Rathinasabapathy, Anandharajan

AU - Bruce, Erin

AU - Gupta, Dipankar

AU - Cardounel, Arturo J.

AU - Mocco, J.

AU - Patel, Jawaharlal M.

AU - Francis, Joseph

AU - Grant, Maria B.

AU - Katovich, Michael J.

AU - Raizada, Mohan K.

PY - 2013/3/15

Y1 - 2013/3/15

N2 - 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.

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KW - ACE2

KW - Angiogenic progenitor cells

KW - Diminazen

KW - Pulmonary hypertension

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