Lentiviral-mediated pulmonary overexpression of Ang-(1-7) significantly attenuated right ventricular systolic pressure and right ventricular hypertrophy in rat models of pulmonary fibrosis and hypertension.
Does overexpression of Ang-(1-7) or ACE2 prevent pulmonary fibrosis and pulmonary hypertension in rat models?
Overexpression of the ACE2/Ang-(1-7)/Mas axis provides cardiopulmonary protection against pulmonary fibrosis and pulmonary hypertension in rat models.
Absolute Event Rate: 47% vs 67.5%
p-value: p=<0.05
RATIONALE: An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme ACE/angiotensin AngII/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders. OBJECTIVES: We hypothesized that Ang-(1-7) treatment would exert protective effects against PF and PH. METHODS: Lentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg). MEASUREMENTS AND MAIN RESULTS: In the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor β and other proinflammatory cytokines, and increased protein levels of the AT₁R. Overexpression of Ang-(1-7) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(1-7) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(1-7) against MCT-induced PH. CONCLUSIONS: Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.
Shenoy et al. (Fri,) conducted a other in Pulmonary Fibrosis and Pulmonary Hypertension. Lentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA vs. Empty virus (control) was evaluated on Right ventricular systolic pressure (RVSP) in MCT-induced pulmonary hypertension (p=<0.05). Lentiviral-mediated pulmonary overexpression of Ang-(1-7) significantly attenuated right ventricular systolic pressure and right ventricular hypertrophy in rat models of pulmonary fibrosis and hypertension.