Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whet...
Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whether Ang-(1-9) improves pulmonary vascular remodeling in monocrotaline (MCT)-induced pulmonary hypertensive rats. Sprague-Dawley rats received Ang-(1-9) ($576{\mu}g/kg/day$) or saline via osmotic mini-pumps for 3 weeks. Three days after implantation of osmotic mini-pumps, 50 mg/kg MCT or vehicle were subcutaneously injected. MCT caused increases in right ventricular weight and systolic pressure, which were reduced by co-administration of Ang-(1-9). Ang-(1-9) also attenuated endothelial damage and medial hypertrophy of pulmonary arterioles as well as pulmonary fibrosis induced by MCT. The protective effects of Ang-(1-9) against pulmonary hypertension were inhibited by Ang type 2 receptor ($AT_2R$) blocker, but not by Mas receptor blocker. Additionally, the levels of LDH and inflammatory cytokines, such as $TNF-{\alpha}$, MCP-1, $IL-1{\beta}$, and IL-6, in plasma were lower in Ang-(1-9) co-treated MCT group than in vehicle-treated MCT group. Changes in expressions of apoptosis-related proteins such as Bax, Bcl2, Caspase-3 and -9 in the lung tissue of MCT rats were attenuated by the treatment with Ang-(1-9). These results indicate that Ang-(1-9) improves MCT-induced pulmonary hypertension by decreasing apoptosis and inflammatory reaction via $AT_2R$.
Angiotensin-(1-9) [Ang-(1-9)], generated from Ang I by Ang II converting enzyme 2, has been reported to have protective effects on cardiac and vascular remodeling. However, there is no report about the effect of Ang-(1-9) on pulmonary hypertension. The aim of the present study is to investigate whether Ang-(1-9) improves pulmonary vascular remodeling in monocrotaline (MCT)-induced pulmonary hypertensive rats. Sprague-Dawley rats received Ang-(1-9) ($576{\mu}g/kg/day$) or saline via osmotic mini-pumps for 3 weeks. Three days after implantation of osmotic mini-pumps, 50 mg/kg MCT or vehicle were subcutaneously injected. MCT caused increases in right ventricular weight and systolic pressure, which were reduced by co-administration of Ang-(1-9). Ang-(1-9) also attenuated endothelial damage and medial hypertrophy of pulmonary arterioles as well as pulmonary fibrosis induced by MCT. The protective effects of Ang-(1-9) against pulmonary hypertension were inhibited by Ang type 2 receptor ($AT_2R$) blocker, but not by Mas receptor blocker. Additionally, the levels of LDH and inflammatory cytokines, such as $TNF-{\alpha}$, MCP-1, $IL-1{\beta}$, and IL-6, in plasma were lower in Ang-(1-9) co-treated MCT group than in vehicle-treated MCT group. Changes in expressions of apoptosis-related proteins such as Bax, Bcl2, Caspase-3 and -9 in the lung tissue of MCT rats were attenuated by the treatment with Ang-(1-9). These results indicate that Ang-(1-9) improves MCT-induced pulmonary hypertension by decreasing apoptosis and inflammatory reaction via $AT_2R$.
* AI 자동 식별 결과로 적합하지 않은 문장이 있을 수 있으니, 이용에 유의하시기 바랍니다.
제안 방법
To evaluate whether the protective effect of Ang-(1-9) in MCT rats is mediated via apoptosis, the expressions of apoptotic-related proteins in lung tissues were measured. Western blot showed that the expressions of Bax, caspase-3, and -9 proteins were increased and the expression of Bcl protein was decreased in lung tissues of MCT rats (Fig.
대상 데이터
Ang-(1-9) was infused 3 days before MCT injection for 24 days at a dose of 576 μg/kg/day via a mini-osmotic pumps (Alzet 2004, Cupertino, CA) implanted subcutaneously between the scapulars [10]. Three days after the start of Ang-(1-9) infusion, MCT was injected. Groups 4 and 5 were MCT-induced PH rats pretreated with Ang-(1-9) in the presence of AT2R or Mas R antagonist.
데이터처리
The results are presented as the mean±SEM. Statistical significance of the differences was assessed using analysis of variance followed by the Bonferroni multiple comparison test. Student’s t test was also used.
Student’s t test was also used.
후속연구
Although current therapies improve symptoms and hemodynamics of PH, true reversal of pulmonary vascular remodeling is rarely achieved. Therefore, further studies are needed to develop more effective therapies to target the abnormal pulmonary vasculature.
3 Flores-Munoz M Work LM Douglas K Denby L Dominiczak AF Graham D Nicklin SA Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor Hypertension 2012 59 300 307 22184331
4 Ocaranza MP Moya J Barrientos V Alzamora R Hevia D Morales C Pinto M Escudero N Garcia L Novoa U Ayala P Diaz-Araya G Godoy I Chiong M Lavandero S Jalil JE Michea L Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis J Hypertens 2014 32 771 783 24463937
5 Ocaranza MP Rivera P Novoa U Pinto M Gonzalez L Chiong M Lavandero S Jalil JE Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension J Hypertens 2011 29 706 715 21330937
6 Jackman HL Massad MG Sekosan M Tan F Brovkovych V Marcic BM Erdos EG Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A Hypertension 2002 39 976 981 12019279
7 Bruce E Shenoy V Rathinasabapathy A Espejo A Horowitz A Oswalt A Francis J Nair A Unger T Raizada MK Steckelings UM Sumners C Katovich MJ Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis Br J Pharmacol 2015 172 2219 2231 25522140
8 Cha SA Park BM Gao S Kim SH Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor Life Sci 2013 93 934 940 24177599
9 Flores-Munoz M Smith NJ Haggerty C Milligan G Nicklin SA Angiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor J Physiol 2011 589 939 951 21173078
10 Oh YB Kim JH Park BM Park BH Kim SH Captopril intake decreases body weight gain via angiotensin-(1-7) Peptides 2012 37 79 85 22743141
11 Gao S Oh YB Shah A Park WH Chung MJ Lee YH Kim SH Urotensin II receptor antagonist attenuates monocrotaline-induced cardiac hypertrophy in rats Am J Physiol Heart Circ Physiol 2010 299 H1782 H1789 20870804
12 Cho KW Kim SH Koh GY Seul KH Huh KS Chu D Rapp NS Moon HB Kim KK Kook YJ Plasma concentration of atrial natriuretic peptide in different phases of Korean hemorrhagic fever Nephron 1989 51 215 219 2563575
13 Nishii Y Gabazza EC Fujimoto H Nakahara H Takagi T Bruno N D'Alessandro-Gabazza CN Maruyama J Maruyama K Hayashi T Adachi Y Suzuki K Taguchi O Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension J Thromb Haemost 2006 4 2331 2339 17059470
15 Ashcroft T Simpson JM Timbrell V Simple method of estimating severity of pulmonary fibrosis on a numerical scale J Clin Pathol 1988 41 467 470 3366935
16 Hubner RH Gitter W El Mokhtari NE Mathiak M Both M Bolte H Freitag-Wolf S Bewig B Standardized quantification of pulmonary fibrosis in histological samples Biotechniques 2008 44 507 511 514 517 18476815
17 Ikeda Y Yonemitsu Y Kataoka C Kitamoto S Yamaoka T Nishida K Takeshita A Egashira K Sueishi K Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats Am J Physiol Heart Circ Physiol 2002 283 H2021 H2028 12384481
18 Ocaranza MP Godoy I Jalil JE Varas M Collantes P Pinto M Roman M Ramirez C Copaja M Diaz-Araya G Castro P Lavandero S Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat Hypertension 2006 48 572 578 16908757
19 Ocaranza MP Lavandero S Jalil JE Moya J Pinto M Novoa U Apablaza F Gonzalez L Hernandez C Varas M Lopez R Godoy I Verdejo H Chiong M Angiotensin-(1-9) regulates cardiac hypertrophy in vivo and in vitro J Hypertens 2010 28 1054 1064 20411619
20 Gomez-Arroyo JG Farkas L Alhussaini AA Farkas D Kraskauskas D Voelkel NF Bogaard HJ The monocrotaline model of pulmonary hypertension in perspective Am J Physiol Lung Cell Mol Physiol 2012 302 L363 L369 21964406
22 Ocaranza MP Michea L Chiong M Lagos CF Lavandero S Jalil JE Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system Clin Sci (Lond) 2014 127 549 557 25029123
23 Stacher E Graham BB Hunt JM Gandjeva A Groshong SD McLaughlin VV Jessup M Grizzle WE Aldred MA Cool CD Tuder RM Modern age pathology of pulmonary arterial hypertension Am J Respir Crit Care Med 2012 186 261 272 22679007
24 Cool CD Kennedy D Voelkel NF Tuder RM Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection Hum Pathol 1997 28 434 442 9104943
25 Shenoy V Ferreira AJ Qi Y Fraga-Silva RA Diez-Freire C Dooies A Jun JY Sriramula S Mariappan N Pourang D Venugopal CS Francis J Reudelhuber T Santos RA Patel JM Raizada MK Katovich MJ 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 1065 1072 20581171
26 Soon E Holmes AM Treacy CM Doughty NJ Southgate L Machado RD Trembath RC Jennings S Barker L Nicklin P Walker C Budd DC Pepke-Zaba J Morrell NW Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension Circulation 2010 122 920 927 20713898
28 Sutendra G Dromparis P Bonnet S Haromy A McMurtry MS Bleackley RC Michelakis ED Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension J Mol Med (Berl) 2011 89 771 783 21809123
29 Marchesi C Paradis P Schiffrin EL Role of the renin-angiotensin system in vascular inflammation Trends Pharmacol Sci 2008 29 367 374 18579222
30 Morrell NW Upton PD Kotecha S Huntley A Yacoub MH Polak JM Wharton J Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors Am J Physiol 1999 277 L440 L448 10484450
31 de Man FS Tu L Handoko ML Rain S Ruiter G Francois C Schalij I Dorfmuller P Simonneau G Fadel E Perros F Boonstra A Postmus PE van der Velden J Vonk-Noordegraaf A Humbert M Eddahibi S Guignabert C Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension Am J Respir Crit Care Med 2012 186 780 789 22859525
32 Wang Y Zhang XH Wang HL Involvement of BMPR2 in the protective effect of fluoxetine against monocrotaline-induced endothelial apoptosis in rats Can J Physiol Pharmacol 2011 89 345 354 21619414
33 Yen CH Leu S Lin YC Kao YH Chang LT Chua S Fu M Wu CJ Sun CK Yip HK Sildenafil limits monocrotaline-induced pulmonary hypertension in rats through suppression of pulmonary vascular remodeling J Cardiovasc Pharmacol 2010 55 574 584 20224427
34 Chen YC Yuan TY Zhang HF Wang DS Yan Y Niu ZR Lin YH Fang LH Du GH Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model Acta Pharmacol Sin 2016 37 772 782 27180980
※ AI-Helper는 부적절한 답변을 할 수 있습니다.