The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension.

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.

[1]  M. Humbert,et al.  Inflammation in pulmonary arterial hypertension , 2003, European Respiratory Journal.

[2]  F. Torti,et al.  Phase I and Pharmacokinetic Study of Angiotensin-(1-7), an Endogenous Antiangiogenic Hormone , 2009, Clinical Cancer Research.

[3]  J. Lasky,et al.  Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[4]  G. Jenkins,et al.  Role of integrin-mediated TGFbeta activation in the pathogenesis of pulmonary fibrosis. , 2009, Biochemical Society transactions.

[5]  M. Raizada,et al.  Prevention of Pulmonary Hypertension by Angiotensin-Converting Enzyme 2 Gene Transfer , 2009, Hypertension.

[6]  N. Weissmann,et al.  Cellular and molecular basis of pulmonary arterial hypertension. , 2009, Journal of the American College of Cardiology.

[7]  M. Raizada,et al.  Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. , 2009, American journal of respiratory and critical care medicine.

[8]  F. Ohsuzu,et al.  Effects of angiotensin on the expression of fibrosis‐associated cytokines, growth factors, and matrix proteins in human lung fibroblasts , 2009, Journal of clinical pharmacy and therapeutics.

[9]  W. Chung,et al.  Polymorphism in the angiotensin II type 1 receptor (AGTR1) is associated with age at diagnosis in pulmonary arterial hypertension. , 2009, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[10]  L. Wilkins.  Late-Breaking Basic Science Abstracts , 2008 .

[11]  M. Raizada,et al.  Angiotensin-(1-7) as an antihypertensive, antifibrotic target , 2008, Current hypertension reports.

[12]  B. Uhal,et al.  Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression , 2008, European Respiratory Journal.

[13]  E. Schiffrin,et al.  Role of the renin-angiotensin system in vascular inflammation. , 2008, Trends in pharmacological sciences.

[14]  B. Uhal,et al.  Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[15]  R. Henning,et al.  Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives. , 2008, European journal of pharmacology.

[16]  C. Berkland,et al.  Inhibition of human lung cancer cell growth by angiotensin II (Ang II) type 2 receptor (AT2) over-expression , 2008 .

[17]  Omer Aras,et al.  Targeting tissue angiotensin-converting enzyme for imaging cardiopulmonary fibrosis , 2008, Current cardiology reports.

[18]  Rui-ming Liu,et al.  Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis. , 2008, Antioxidants & redox signaling.

[19]  S. Antoniu.  Targeting the angiotensin pathway in idiopathic pulmonary fibrosis. , 2008, Expert opinion on therapeutic targets.

[20]  U. Ikeda,et al.  Interleukin-10 Expression Mediated by an Adeno-Associated Virus Vector Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats , 2007, Circulation research.

[21]  B. Uhal,et al.  Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages. , 2007, Current pharmaceutical design.

[22]  M. Raizada,et al.  Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). , 2007, American journal of physiology. Heart and circulatory physiology.

[23]  Hui Wang,et al.  Early lung injury contributes to lung fibrosis via AT1 receptor in rats , 2007, Acta Pharmacologica Sinica.

[24]  M. Raizada,et al.  ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. , 2007, Clinical science.

[25]  M. Raizada,et al.  ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. , 2006, Physiological genomics.

[26]  Naftali Kaminski,et al.  Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. , 2006, American journal of respiratory and critical care medicine.

[27]  J. Loscalzo,et al.  Pulmonary arterial hypertension. , 2004, Annals of medicine.

[28]  B. Greenberg,et al.  Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. , 2005, American journal of physiology. Heart and circulatory physiology.

[29]  D. Badesch,et al.  Evaluation and Management of the Patient with Pulmonary Arterial Hypertension , 2005, Annals of Internal Medicine.

[30]  Mark Chappell,et al.  A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury , 2005, Nature Medicine.

[31]  S. Kudoh,et al.  Interferon-{beta} inhibits bleomycin-induced lung fibrosis by decreasing transforming growth factor-{beta} and thrombospondin. , 2005, American journal of respiratory cell and molecular biology.

[32]  E. Tallant,et al.  Inhibition of human lung cancer cell growth by angiotensin-(1-7). , 2004, Carcinogenesis.

[33]  P. Puri,et al.  Genetic polymorphisms of angiotensin system genes in congenital diaphragmatic hernia associated with persistent pulmonary hypertension. , 2004, Journal of pediatric surgery.

[34]  R. Chambers,et al.  Angiotensin II and the fibroproliferative response to acute lung injury. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[35]  S. Abe,et al.  Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist , 2003, Thorax.

[36]  Thomas Walther,et al.  Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Vancheri,et al.  Role of oxidative stress in pulmonary fibrosis. , 2002, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace.

[38]  J. Catravas,et al.  Pulmonary capillary endothelial dysfunction in early systemic sclerosis. , 2001, Arthritis and rheumatism.

[39]  M. Clark,et al.  Angiotensin-(1-7) Downregulates the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells , 2001, Hypertension.

[40]  M. Yacoub,et al.  Expression of pulmonary vascular angiotensin‐converting enzyme in primary and secondary plexiform pulmonary hypertension , 2000, The Journal of pathology.

[41]  G. Laurent,et al.  Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. , 2000, American journal of respiratory and critical care medicine.

[42]  David A. Lynch,et al.  Idiopathic pulmonary fibrosis: Diagnosis and treatment: International Consensus Statement , 2000 .

[43]  G. Filippatos,et al.  Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[44]  D. Ganten,et al.  Converting enzyme determines plasma clearance of angiotensin-(1-7). , 1998, Hypertension.

[45]  G. Chisolm,et al.  Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. , 1996, Hypertension.

[46]  D. Ganten,et al.  Effect of losartan on right ventricular hypertrophy and cardiac angiotensin I-converting enzyme activity in pulmonary hypertensive rats. , 1996, Clinical and experimental hypertension.

[47]  B. Lipworth,et al.  The role of the renin-angiotensin and natriuretic peptide systems in the pulmonary vasculature. , 1995, British journal of clinical pharmacology.

[48]  M. Gillespie,et al.  Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist. , 1992, The Journal of pharmacology and experimental therapeutics.

[49]  S. Burne,et al.  Bleomycin regulation of transforming growth factor-beta mRNA in rat lung fibroblasts. , 1992, American journal of respiratory cell and molecular biology.

[50]  J M Simpson,et al.  Simple method of estimating severity of pulmonary fibrosis on a numerical scale. , 1988, Journal of clinical pathology.

[51]  J. Lazo.  Endothelial injury caused by antineoplastic agents. , 1986, Biochemical pharmacology.

[52]  R. Newman,et al.  Assessment of bleomycin lung toxicity using angiotensin-converting enzyme in pulmonary lavage. , 1980, Cancer research.

[53]  W. O’Brien,et al.  Modified assay for determination of hydroxyproline in a tissue hydrolyzate. , 1980, Clinica chimica acta; international journal of clinical chemistry.