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The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension.
Am J Respir Crit Care Med. 2010 Oct 15; 182(8):1065-72.AJ

Abstract

RATIONALE

An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/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.

Authors+Show Affiliations

Department of Pharmacodynamics, University of Florida, Gainesville, Florida, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Evaluation Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20581171

Citation

Shenoy, Vinayak, et al. "The Angiotensin-converting Enzyme 2/angiogenesis-(1-7)/Mas Axis Confers Cardiopulmonary Protection Against Lung Fibrosis and Pulmonary Hypertension." American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 8, 2010, pp. 1065-72.
Shenoy V, Ferreira AJ, Qi Y, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. 2010;182(8):1065-72.
Shenoy, V., Ferreira, A. J., Qi, Y., Fraga-Silva, R. A., Díez-Freire, C., Dooies, A., Jun, J. Y., Sriramula, S., Mariappan, N., Pourang, D., Venugopal, C. S., Francis, J., Reudelhuber, T., Santos, R. A., Patel, J. M., Raizada, M. K., & Katovich, M. J. (2010). The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 182(8), 1065-72. https://doi.org/10.1164/rccm.200912-1840OC
Shenoy V, et al. The Angiotensin-converting Enzyme 2/angiogenesis-(1-7)/Mas Axis Confers Cardiopulmonary Protection Against Lung Fibrosis and Pulmonary Hypertension. Am J Respir Crit Care Med. 2010 Oct 15;182(8):1065-72. PubMed PMID: 20581171.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. AU - Shenoy,Vinayak, AU - Ferreira,Anderson J, AU - Qi,Yanfei, AU - Fraga-Silva,Rodrigo A, AU - Díez-Freire,Carlos, AU - Dooies,Autumn, AU - Jun,Joo Yun, AU - Sriramula,Srinivas, AU - Mariappan,Nithya, AU - Pourang,Dorna, AU - Venugopal,Changaram S, AU - Francis,Joseph, AU - Reudelhuber,Timothy, AU - Santos,Robson A, AU - Patel,Jawaharlal M, AU - Raizada,Mohan K, AU - Katovich,Michael J, Y1 - 2010/06/25/ PY - 2010/6/29/entrez PY - 2010/6/29/pubmed PY - 2010/11/16/medline SP - 1065 EP - 72 JF - American journal of respiratory and critical care medicine JO - Am J Respir Crit Care Med VL - 182 IS - 8 N2 - RATIONALE: An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/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. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/20581171/The_angiotensin_converting_enzyme_2/angiogenesis__1_7_/Mas_axis_confers_cardiopulmonary_protection_against_lung_fibrosis_and_pulmonary_hypertension_ L2 - https://www.atsjournals.org/doi/10.1164/rccm.200912-1840OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -