Diminazene Attenuates Pulmonary Hypertension and Improves Angiogenic Progenitor Cell Functions in Experimental Models

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 "offtarget" 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 1a, which was corrected by in vitro DIZE treatment. Conclusions: Our results identify a therapeutic potential of DIZE in PH therapy.Keywords: pulmonary hypertension; ACE2; angiogenic progenitor cells; diminazene Pulmonary hypertension (PH) is a life-threatening disease characterized by elevated pressure in the pulmonary arteries and What This Study Adds to the FieldWe show that diminazene, an antitrypanosomal drug, attenuates hemodynamic changes, prevents maladaptive right ventricular remodeling, and enhances pulmonary vasorelaxation in experimental models of PH through activation of ACE2. Furthermore, diminazene improves the functions of APCs obtained from experimental animals and patients with PH. This study identifies a new application for an existing drug, which could be successfully developed for PH therapeutics.

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

“…Recently, ACE2 priming by the pharmacological activator, xanthenone (XNT), has been shown to protect the function of endothelial progenitor cells in hypertension and diabetes (5,11,18,23). In the present study, we have used a newly discovered ACE2 activator, DIZE (20,40,46), and shown that it enhances ACE2 activity in vitro. Chronic DIZE treatment elevated the activity of local vascular ACE2, subsequently increased the production of Ang (1-7), and augmented both EDRs in conduit aortas and FMD in resistance arteries from db/db mice.…”

Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade

“…In regard to the benefits of an activated ACE2 pathway, several compounds have been identified that may act as allosteric activators of ACE2 including xanthenone (XNT) and diminazene aceturate (DIZE) to promote a higher ratio of Ang-(1-7) to Ang II [86]. Chronic treatment with DIZE ameliorated the extent of pulmonary hypertensin and fibrosis, renal tissue injury, and myocardial infarction consistent with enhanced levels of Ang-(1-7) and a reduction in Ang II [84,[87][88][89][90]. Interestingly, DIZE treatment was also associated with increased mRNA levels of ACE2 suggesting that DIZE may exhibit actions apart from the direct activation of the peptidase [87,91].…”

New Components of the Renin-Angiotensin-Aldosterone System and Oxidative Stress

“…Efficacy of synthetic enhancers of ACE2 activators, xanthenone (XNT), and resorcinolnaphthalein are reported to activate ACE2, decrease blood pressure, and reverse tissue remodeling [77], and diminazene aceturate (DIZE) to attenuate pulmonary hypertension in experimental models [78]. But some structural modifications are necessary for clinical use because of poor solubility in water and safety.…”