The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Angiotensin-(1-9) ameliorates pulmonary arterial hypertension via angiotensin type II receptor

  • Cha, Seung Ah (Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School) ;
  • Park, Byung Mun (Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School) ;
  • Kim, Suhn Hee (Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School)
  • Received : 2018.03.14
  • Accepted : 2018.04.16
  • Published : 2018.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

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 $AT_2R$.

Keywords

References

  1. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2008;118:2372-2379. https://doi.org/10.1172/JCI33452
  2. Marshall RP. The pulmonary renin-angiotensin system. Curr Pharm Des. 2003;9:715-722. https://doi.org/10.2174/1381612033455431
  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. https://doi.org/10.1161/HYPERTENSIONAHA.111.177485
  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. https://doi.org/10.1097/HJH.0000000000000094
  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. https://doi.org/10.1097/HJH.0b013e3283440665
  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. https://doi.org/10.1161/01.HYP.0000017283.67962.02
  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. https://doi.org/10.1111/bph.13044
  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. https://doi.org/10.1016/j.lfs.2013.10.020
  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. https://doi.org/10.1113/jphysiol.2010.203075
  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. https://doi.org/10.1016/j.peptides.2012.06.005
  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:H1782-1789. https://doi.org/10.1152/ajpheart.00438.2010
  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. https://doi.org/10.1159/000185288
  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. https://doi.org/10.1111/j.1538-7836.2006.02174.x
  14. Schultze AE, Gunaga KP, Wagner JG, Hoorn CM, Moorehead WR, Roth RA. Lactate dehydrogenase activity and isozyme patterns in tissues and bronchoalveolar lavage fluid from rats treated with monocrotaline pyrrole. Toxicol Appl Pharmacol. 1994;126:301-310. https://doi.org/10.1006/taap.1994.1120
  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. https://doi.org/10.1136/jcp.41.4.467
  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;44:507-1, 514-7. https://doi.org/10.2144/000112729
  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:H2021-2028. https://doi.org/10.1152/ajpheart.00919.2001
  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. https://doi.org/10.1161/01.HYP.0000237862.94083.45
  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. https://doi.org/10.1097/HJH.0b013e328335d291
  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:L363-369. https://doi.org/10.1152/ajplung.00212.2011
  21. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006;99:675-691. https://doi.org/10.1161/01.RES.0000243584.45145.3f
  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. https://doi.org/10.1042/CS20130449
  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. https://doi.org/10.1164/rccm.201201-0164OC
  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. https://doi.org/10.1016/S0046-8177(97)90032-0
  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. https://doi.org/10.1164/rccm.200912-1840OC
  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. https://doi.org/10.1161/CIRCULATIONAHA.109.933762
  27. Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. J Lab Clin Med. 1998;132:16-24. https://doi.org/10.1016/S0022-2143(98)90020-8
  28. Sutendra G, Dromparis P, Bonnet S, Haromy A, McMurtry MS, Bleackley RC, Michelakis ED. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNF${\alpha}$ contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med (Berl). 2011;89:771-783. https://doi.org/10.1007/s00109-011-0762-2
  29. Marchesi C, Paradis P, Schiffrin EL. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008;29:367-374. https://doi.org/10.1016/j.tips.2008.05.003
  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:L440-448.
  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. https://doi.org/10.1164/rccm.201203-0411OC
  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. https://doi.org/10.1139/y11-024
  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. https://doi.org/10.1097/FJC.0b013e3181d9f5f4
  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. https://doi.org/10.1038/aps.2016.22

Cited by

  1. Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions vol.9, pp.None, 2018, https://doi.org/10.7554/elife.61330
  2. Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury vol.319, pp.2, 2018, https://doi.org/10.1152/ajplung.00189.2020
  3. Research progress on small peptides in Chinese Baijiu vol.72, pp.None, 2018, https://doi.org/10.1016/j.jff.2020.104081
  4. Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome vol.21, pp.21, 2018, https://doi.org/10.3390/ijms21218038
  5. A Potential Role of the Renin-Angiotensin-System for Disturbances of Respiratory Chemosensitivity in Acute Respiratory Distress Syndrome and Severe Acute Respiratory Syndrome vol.11, pp.None, 2018, https://doi.org/10.3389/fphys.2020.588248
  6. Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes vol.10, pp.5, 2018, https://doi.org/10.3390/antiox10050779
  7. 2020 update on the renin-angiotensin-aldosterone system in pediatric kidney disease and its interactions with coronavirus vol.36, pp.6, 2018, https://doi.org/10.1007/s00467-020-04759-1
  8. Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19 vol.39, pp.6, 2021, https://doi.org/10.1038/s41587-020-00796-1
  9. Food-Derived Bioactive Peptides: A Promising Substitute to Chemosynthetic Drugs Against the Dysregulated Renin-Angiotensin System in COVID-19 Patients vol.11, pp.4, 2018, https://doi.org/10.1080/22311866.2021.1945494