title: ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats.
abstract: BACKGROUND
  Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats.
  
  
  METHODS
  Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH-related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting.
  
  
  RESULTS
  Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1-7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1-7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779.
  
  
  CONCLUSIONS
  These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system.
authors: Pediatric Cardiac Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
authors: Gang
authors: G
authors: Li
authors: Yinglong
authors: Y
authors: Liu
authors: Yaobin
authors: Y
authors: Zhu
authors: Aijun
authors: A
authors: Liu
authors: Yulin
authors: Y
authors: Xu
authors: Xiaofeng
authors: X
authors: Li
authors: Zhiqiang
authors: Z
authors: Li
authors: Junwu
authors: J
authors: Su
authors: Lizhong
authors: L
authors: Sun
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D016686:Monocrotaline; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D058426:Neointima; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology*; D012720:Severity of Illness Index; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D020536:Enzyme Activators; D009281:Naphthalenes; D010446:Peptide Fragments; D012118:Resorcinols; D000804:Angiotensin II; C031721:naphthalene; D016686:Monocrotaline; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); C031389:resorcinol
references: Am J Physiol. 1998 Apr;274(4):H1218-29
references: 9575925
references: Life Sci. 2006 Apr 4;78(19):2166-71
references: 16303146
references: Curr Pharm Des. 2003;9(9):715-22
references: 12570789
references: Circ J. 2011;75(8):1801-10
references: 21747194
references: J Biol Chem. 2002 Apr 26;277(17):14838-43
references: 11815627
references: Hypertens Res. 2008 Mar;31(3):553-9
references: 18497476
references: Chin Med J (Engl). 2012 Apr;125(8):1381-8
references: 22613639
references: Circulation. 2003 Sep 30;108(13):1640-5
references: 12963647
references: Hypertension. 2007 Jan;49(1):185-92
references: 17116756
references: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15886-91
references: 20798044
references: Circ J. 2011;75(6):1287-96
references: 21532177
references: Hypertension. 2007 Dec;50(6):1093-8
references: 17984366
references: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):650-7
references: 14764423
references: Am J Physiol. 1996 Jan;270(1 Pt 2):H364-75
references: 8769773
references: Hypertension. 2008 Nov;52(5):967-73
references: 18809792
references: Am J Respir Crit Care Med. 2009 Jun 1;179(11):1048-54
references: 19246717
references: Curr Hypertens Rep. 2010 Aug;12(4):212-9
references: 20556668
references: Hypertens Res. 2010 Nov;33(11):1182-5
references: 20703229
references: Curr Opin Pharmacol. 2011 Apr;11(2):150-5
references: 21215698
references: Br J Pharmacol. 2008 Jan;153(1):66-74
references: 17906677
references: Hypertension. 2008 May;51(5):1312-7
references: 18391097
references: J Pharmacol Exp Ther. 1998 Jan;284(1):388-98
references: 9435202
references: J Clin Invest. 2005 Oct;115(10):2811-21
references: 16200212
references: Zhonghua Yi Xue Za Zhi. 2011 Jan 11;91(2):125-8
references: 21418997
references: Swiss Med Wkly. 2007 Aug 11;137(31-32):437-42
references: 17705107
references: Peptides. 2005 Jul;26(7):1270-7
references: 15949646
references: Am J Pathol. 1997 Oct;151(4):1019-25
references: 9327735
references: Circ J. 2010 Mar;74(3):405-10
references: 20134095
references: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1377-84
references: 18660448
references: Exp Physiol. 2011 Mar;96(3):287-94
references: 21148624
references: Am J Respir Crit Care Med. 2010 Oct 15;182(8):1065-72
references: 20581171
references: Hypertension. 2009 Aug;54(2):365-71
references: 19564552
references: Circ J. 2011;75(6):1463-71
references: 21498912