Selective activation of angiotensin AT₂ receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis

Abstract

Background and Purpose Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right‐heart failure and death. A dys‐regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non‐peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well‐established monocrotaline (MCT) rat model of PH. Experimental Approach A single s.c. injection of MCT (50 mg·kg−1) was used to induce PH in 8‐week‐old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg−1 C21, 3 mg·kg−1 PD‐123319 or 0.5 mg·kg−1 A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. Key Results Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT‐induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro‐inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co‐administration of the AT2 receptor antagonist, PD‐123319, or the Mas antagonist, A779, abolished the protective actions of C21. Conclusions and Implications Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH.

Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia

“…Overexpression of AT2R also upregulates the ACE2 levels in the ischemic heart [43]. The Ang-(1–7) receptor, Mas R, can functionally interact with AT2R [42], and a Mas R blocker abolished the C21-mediated protective effects in a rat model of pulmonary hypertension [44]. In this context, we observed upregulation of AT2R in the ACE2 KI animals.…”

Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

“…In line with this, a study by Imai and colleagues showed that Agtr2-knockout mice had more severe pathology in response to acid aspiration induced lung injury than wild-type controls [34]. A number of beneficial actions of AT2R in lung injury have recently been demonstrated [52][53][54]. Bruce and colleagues found that treatment with C21, an AT2R non-peptide agonist, ameliorates pulmonary fibrosis and prevents right ventricular fibrosis in pulmonary hypertension, and these beneficial effects are abolished by co-administration of the AT2R antagonist, PD123319 [52].…”

“…A number of beneficial actions of AT2R in lung injury have recently been demonstrated [52][53][54]. Bruce and colleagues found that treatment with C21, an AT2R non-peptide agonist, ameliorates pulmonary fibrosis and prevents right ventricular fibrosis in pulmonary hypertension, and these beneficial effects are abolished by co-administration of the AT2R antagonist, PD123319 [52]. Furthermore, Rathinasabapathy and colleagues found that stimulation of the AT2R by C21 attenuates bleomycin-induced lung injury by alleviating lung inflammation and fibrosis [53].…”

Nicotine and the renin-angiotensin system

“…Both ACE2 and MasR are predominantly expressed by bronchial epithelial cells (75,150), although alveolar epithelial cells, vascular endothelial cells, and VSMCs are also positive for ACE2 (59). In addition to pulmonary arterial hypertension (PAH) (30,97), the lung RAS is involved in the pathogenesis of many other lung diseases unrelated to BP and fluid balance, which include lung infection/inflammation (74), acute lung injury/acute respiratory distress syndrome (70), COPD (60,123), and pulmonary fibrosis (12,137,138).…”