title: Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia.
abstract: The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT₁) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT₁receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT₁receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.
authors.affiliation: Department of Physiology and Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. E-mail: luce@medicon.cz.
authors.forename: V
authors.initials: V
authors.lastname: Hampl
authors.forename: J
authors.initials: J
authors.lastname: Herget
authors.forename: J
authors.initials: J
authors.lastname: Bíbová
authors.forename: A
authors.initials: A
authors.lastname: Baňasová
authors.forename: Z
authors.initials: Z
authors.lastname: Husková
authors.forename: Z
authors.initials: Z
authors.lastname: Vaňourková
authors.forename: Š
authors.initials: Š
authors.lastname: Jíchová
authors.forename: P
authors.initials: P
authors.lastname: Kujal
authors.forename: Z
authors.initials: Z
authors.lastname: Vernerová
authors.forename: J
authors.initials: J
authors.lastname: Sadowski
authors.forename: L
authors.initials: L
authors.lastname: Červenka
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D062186:Arterial Pressure; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D008168:Lung / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; C473112:Ren2 protein, mouse; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; C118790:angiotensin I (1-7)