Evidence for Angiotensin-converting Enzyme 2 as a Therapeutic Target for the Prevention of Pulmonary Hypertension
- 1 June 2009
- journal article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 179 (11), 1048-1054
- https://doi.org/10.1164/rccm.200811-1678oc
Abstract
It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.This publication has 30 references indexed in Scilit:
- Role of the renin–angiotensin system in vascular inflammationTrends in Pharmacological Sciences, 2008
- Molecular pathogenesis of pulmonary arterial hypertensionJCI Insight, 2008
- Circulating Endothelial Microparticle Levels Predict Hemodynamic Severity of Pulmonary HypertensionAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase PathwayThe American Journal of Pathology, 2008
- Structure-Based Identification of Small-Molecule Angiotensin-Converting Enzyme 2 Activators as Novel Antihypertensive AgentsHypertension, 2008
- Pulmonary Arterial HypertensionJournal of the American College of Cardiology, 2008
- Pulmonary hypertension associated with COPDInternational Journal of Chronic Obstructive Pulmonary Disease, 2008
- Pathogenic mechanisms of pulmonary arterial hypertensionJournal of Molecular and Cellular Cardiology, 2008
- The emerging role of ACE2 in physiology and diseaseThe Journal of Pathology, 2007
- Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lungJournal of Cellular Biochemistry, 2007