Skip to main content
SpringerLink
Log in

Angiotensin-(1-12): A Chymase-Mediated Cellular Angiotensin II Substrate

  • Hypertension and the Kidney(R Carey, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

The classical view of biochemical pathways for the formation of biologically active angiotensins continues to undergo significant revision as new data uncovers the existence of important species differences between humans and rodents. The discovery of two novel substrates that, cleaved from angiotensinogen, can lead to direct tissue angiotensin II formation has the potential of radically altering our understanding of how tissues source angiotensin II production and explain the relative lack of efficacy that characterizes the use of angiotensin converting enzyme inhibitors in cardiovascular disease. This review addresses the discovery of angiotensin-(1-12) as an endogenous substrate for the production of biologically active angiotensin peptides by a non-renin dependent mechanism and the revealing role of cardiac chymase as the angiotensin II convertase in the human heart. This new information provides a renewed argument for exploring the role of chymase inhibitors in the correction of cardiac arrhythmias and left ventricular systolic and diastolic dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci. 2004;61(21):2720–7.

    Article  CAS  PubMed  Google Scholar 

  2. Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006;7(1):3–14.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrario CM. New physiological concepts of the renin-angiotensin system from the investigation of precursors and products of angiotensin I metabolism. Hypertension. 2010;55(2):445–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Schiavone MT, Santos RA, Brosnihan KB, et al. Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide. Proc Natl Acad Sci U S A. 1988;85(11):4095–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Ferrario CM, Ahmad S, Nagata S, et al. An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond). 2014;126(7):461–9.

    Article  CAS  Google Scholar 

  6. Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol. 2005;289(6):H2281–90.

    Article  CAS  PubMed  Google Scholar 

  7. Ferrario CM. Angiotensin-converting enzyme 2 and angiotensin-(1-7): an evolving story in cardiovascular regulation. Hypertension. 2006;47(3):515–21.

    Article  CAS  PubMed  Google Scholar 

  8. Ferrario CM, Varagic J. The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am J Physiol Renal Physiol. 2010;298(6):F1297–305.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Santos RA, Ferreira AJ, Verano-Braga T, et al. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013;216(2):R1–17.

    Article  CAS  PubMed  Google Scholar 

  10. Paul M, Poyan MA, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86(3):747–803.

    Article  CAS  PubMed  Google Scholar 

  11. Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Rice GI, Jones AL, Grant PJ, et al. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension. 2006;48(5):914–20.

    Article  CAS  PubMed  Google Scholar 

  13. Carey RM. Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age. Hypertension. 2005;45(5):840–4.

    Article  CAS  PubMed  Google Scholar 

  14. Carey RM. Newly discovered components and actions of the renin-angiotensin system. Hypertension. 2013;62(5):818–22. This review article provides a timely perspective of the components and actions of the renin angiotensin system, including receptor mechanisms.

    Article  CAS  PubMed  Google Scholar 

  15. Carey RM, Padia SH. Role of angiotensin AT(2) receptors in natriuresis: Intrarenal mechanisms and therapeutic potential. Clin Exp Pharmacol Physiol. 2013;40(8):527–34.

    Article  CAS  PubMed  Google Scholar 

  16. Lautner RQ, Villela DC, Fraga-Silva RA, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11. Biological effects are demonstrated for an heptapeptide where the sequence of Ang-(1-7) is modified at the N-terminus by the substitution of aspartic by alanine in position 1. The heptapeptide has a preference for the Mas-related G-protein–coupled receptor, member D.

    Article  CAS  PubMed  Google Scholar 

  17. Villela DC, Passos-Silva DG, Santos RA. Alamandine: a new member of the angiotensin family. Curr Opin Nephrol Hypertens. 2014;23(2):130–4.

    Article  CAS  PubMed  Google Scholar 

  18. Clarke C, Flores-Munoz M, McKinney CA, et al. Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensin system. Futur Cardiol. 2013;9(1):23–38.

    Article  CAS  Google Scholar 

  19. Flores-Munoz M, Godinho BM, Almalik A, et al. Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor. PLoS One. 2012;7(9):e45564.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ocaranza MP, Moya J, Barrientos V et al. Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis. J Hypertens 2014.

  21. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336(7653):1121–3.

    Article  PubMed  Google Scholar 

  22. Disertori M, Barlera S, Staszewsky L, et al. Systematic review and meta-analysis: renin-Angiotensin system inhibitors in the prevention of atrial fibrillation recurrences: an unfulfilled hope. Cardiovasc Drugs Ther. 2012;26(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  23. Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951–8.

    Article  PubMed  Google Scholar 

  24. Scheen AJ, Krzesinski JM. ONTARGET: similar protection of telmisartan and ramipril and lack of benefit of combined therapy in patients at high risk for vascular events. Rev Med Liege. 2008;63(4):213–9.

    CAS  PubMed  Google Scholar 

  25. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.

    Article  CAS  PubMed  Google Scholar 

  26. Messerli FH, Bangalore S. ALTITUDE trial and dual RAS blockade: the alluring but soft science of the surrogate end point. Am J Med. 2013;126(3):e1–3.

    Article  PubMed  Google Scholar 

  27. Sever P. Hypotension and ischaemic stroke associated with aliskiren in the ALTITUDE trial: sensitisation of the Bezold-Jarisch reflex? J Renin Angiotensin Aldosterone Syst. 2013;14(1):1–2.

    Article  PubMed  Google Scholar 

  28. Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med. 2007;167(18):1930–6.

    Article  CAS  PubMed  Google Scholar 

  29. Nagata S, Hatakeyama K, Asami M, et al. Big angiotensin-25: A novel glycosylated angiotensin-related peptide isolated from human urine. Biochem Biophys Res Commun. 2013;441(4):757–62. By screening human urine gel filtration fractions for bioactive peptides using an antibody raised against the N-terminal portion of Ang II, these investigators discovered the existence of an extended form of Ang I consisting of the first 25 amino acids of the angiotensinogen molecule. Ang-(1-25) is expressed in most human tissues and it is cleaved into Ang II by chymase. The demonstration that Ang-(1-25) is N-glycosylated on its 14th amino acid (Asn) and has a cysteine linked to its 18th amino acid (Cys) is used as evidence that the peptide is expressed in humans but not rodents.

    Article  CAS  PubMed  Google Scholar 

  30. Nagata S, Kato J, Sasaki K, et al. Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system. Biochem Biophys Res Commun. 2006;350(4):1026–31.

    Article  CAS  PubMed  Google Scholar 

  31. Jessup JA, Trask AJ, Chappell MC, et al. Localization of the novel angiotensin peptide, angiotensin-(1-12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2008;294(6):H2614–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Komatsu Y, Kida N, Nozaki N, et al. Effects of proangiotensin-12 infused continuously over 14 days in conscious rats. Eur J Pharmacol. 2012;683(1-3):186–9. This well conducted study shows that Ang-(1-12) has long-term pressor activity, a finding that suggest that this extended form of Ang I is able to generate Ang II endogenously.

    Article  CAS  PubMed  Google Scholar 

  33. Isa K, Garcia-Espinosa MA, Arnold AC, et al. Chronic immunoneutralization of brain angiotensin-(1-12) lowers blood pressure in transgenic (mRen2)27 hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2009;297(1):R111–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Arnold AC, Isa K, Shaltout HA, et al. Angiotensin-(1-12) requires angiotensin converting enzyme and AT1 receptors for cardiovascular actions within the solitary tract nucleus. Am J Physiol Heart Circ Physiol. 2010;299(3):H763–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Chitravanshi VC, Sapru HN. Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat. Am J Physiol Heart Circ Physiol. 2011;300(1):H230–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Chitravanshi VC, Proddutur A, Sapru HN. Cardiovascular actions of angiotensin-(1-12) in the hypothalamic paraventricular nucleus of the rat are mediated via angiotensin II. Exp Physiol. 2012;97(9):1001–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol. 2011;300(3):H951–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Arakawa H, Kawabe K, Sapru HN. Angiotensin-(1-12) in the rostral ventrolateral medullary pressor area of the rat elicits sympathoexcitatory responses. Exp Physiol. 2013;98(1):94–108. Extending the series of studies showing Ang-(1-12) biological effects in brain nuclei influencing the brain regulation of blood pressure, these investigators describe that Ang-(1-12) elicits pressor response associated with increased splachnic nerve sympathetic discharges during microinjections of the peptide in this critical region of the rostral medulla oblongata. Adding weight to the dual role of ACE and chymase, the investigators showed that both enzymes are required for Ang-(1-12) metabolism into Ang II.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Prosser HC, Forster ME, Richards AM, et al. Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics. Cardiovasc Res. 2009;82(1):40–50.

    Article  CAS  PubMed  Google Scholar 

  40. Prosser HC, Richards AM, Forster ME, et al. Regional vascular response to ProAngiotensin-12 (PA12) through the rat arterial system. Peptides. 2010;31(8):1540–5.

    Article  CAS  PubMed  Google Scholar 

  41. Moniwa N, Varagic J, Simington SW, et al. Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism. Am J Physiol Heart Circ Physiol. 2013;305(5):H644–50.

    Article  CAS  PubMed  Google Scholar 

  42. Ahmad S, Varagic J, Westwood BM, et al. Uptake and metabolism of the novel peptide angiotensin-(1-12) by neonatal cardiac myocytes. PLoS One. 2011;6(1):e15759. This study represents the first publication that identifies Ang-(1-12) metabolic pathways in cardiac myocytes and shows increased Ang-(1-12) uptake in SHR compared with WKY.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Westwood BM, Chappell MC. Divergent pathways for the angiotensin-(1-12) metabolism in the rat circulation and kidney. Peptides. 2012;35(2):190–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ouimet T, Facchinetti P, Rose C, et al. Neprilysin II: A putative novel metalloprotease and its isoforms in CNS and testis. Biochem Biophys Res Commun. 2000;271(3):565–70.

    Article  CAS  PubMed  Google Scholar 

  45. Varagic J, Ahmad S, Voncannon JL, et al. Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats. Am J Hypertens. 2013;26(5):583–90. While the focus of this study is on the potential contribution of the ACE2/Ang-(1-7)/mas-axis to the antihypertensive actions of the AT1-receptor antagonist, olmesartan, Table 2 documents that renal neprilysin activity is greater than 95-fold above those measured for renal ACE activity in a transgenic model of renin-dependent hypertension.

    Article  CAS  PubMed  Google Scholar 

  46. Cook JL, Re RN. Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model. Am J Physiol Regul Integr Comp Physiol. 2012;302(5):R482–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Re RN. Tissue renin angiotensin systems. Med Clin North Am. 2004;88(1):19–38.

    Article  CAS  PubMed  Google Scholar 

  48. Re RN, Cook JL. Noncanonical intracrine action. J Am Soc Hypertens. 2011;5(6):435–48. A strong position paper detailing the biological significance of intracrine mechanisms in health and disease from one of the major leaders in this field.

    Article  CAS  PubMed  Google Scholar 

  49. Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system: a new paradigm. Trends Endocrinol Metab. 2007;18(5):208–14.

    Article  CAS  PubMed  Google Scholar 

  50. Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system: implications in cardiovascular remodeling. Curr Opin Nephrol Hypertens. 2008;17(2):168–73.

    Article  CAS  PubMed  Google Scholar 

  51. Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system in the heart. Curr Hypertens Rep. 2009;11(2):104–10.

    Article  CAS  PubMed  Google Scholar 

  52. Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res. 1999;85(7):643–50.

    Article  CAS  PubMed  Google Scholar 

  53. De Mello WC, Frohlich ED. On the local cardiac renin angiotensin system. Basic and clinical implications. Peptides. 2011;32(8):1774–9.

    Article  PubMed  Google Scholar 

  54. De Mello WC. Mechanical stretch reduces the effect of angiotensin II on potassium current in cardiac ventricular cells of adult Sprague Dawley rats. On the role of AT1 receptors as mechanosensors. J Am Soc Hypertens. 2012;6(6):369–74. This important paper reviews De Mello original studies showing that AT1 receptors functioning as mechanoreceptors sensing changes in cell volume can become a major source for cardiac arrhythmias.

    Article  PubMed  Google Scholar 

  55. Dell'Italia LJ, Meng QC, Balcells E, et al. Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation. Am J Physiol. 1995;269(6 Pt 2):H2065–73.

    PubMed  Google Scholar 

  56. Ferrario CM. Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin-angiotensin-aldosterone system: antihypertensive effects and benefits beyond BP control. Life Sci. 2010;86(9–10):289–99.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–10.

    Article  CAS  PubMed  Google Scholar 

  58. Ahmad S, Simmons T, Varagic J, et al. Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue. PLoS One. 2011;6(12):e28501. This study in human atrial tissue from patients undergoing heart surgery for the treatment of resistant atrial fibrillation created the underpinning for a pathogenic role of myocyte Ang-(1-12) as the principal source accounting for the role of Ang II in the generation of cardiac arrthymias. The studies include demonstration of chymase as the Ang-(1-12) converting enzyme in human atrial tissue.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Ahmad S, Wei CC, Tallaj J, et al. Chymase mediates angiotensin-(1-12) metabolism in normal human hearts. J Am Soc Hypertens. 2013;7(2):128–36. Extending the prior conclusions obtained in human disease atrial tissue, the study confirms that chymase is the sole enzyme accounting for Ang-(1-12) metabolism to Ang II directly.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Hoshino F, Urata H, Inoue Y, et al. Chymase inhibitor improves survival in hamsters with myocardial infarction. J Cardiovasc Pharmacol. 2003;41 Suppl 1:S11–8.

    CAS  PubMed  Google Scholar 

  61. Wei CC, Hase N, Inoue Y, et al. Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2010;120(4):1229–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension. 2000;36(4):638–41.

    Article  CAS  PubMed  Google Scholar 

  63. Ihara M, Urata H, Kinoshita A, et al. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension. 1999;33(6):1399–405.

    Article  CAS  PubMed  Google Scholar 

  64. Rafiq K, Sherajee SJ, Fan YY, et al. Blood glucose level and survival in streptozotocin-treated human chymase transgenic mice. Chin J Physiol. 2011;54(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  65. Hara M, Ono K, Hwang MW, et al. Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med. 2002;195(3):375–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Kokkonen JO, Lindstedt KA, Kovanen PT. Role for chymase in heart failure: angiotensin II-dependent or -independent mechanisms? Circulation. 2003;107(20):2522–4.

    Article  PubMed  Google Scholar 

  67. Matsumoto T, Wada A, Tsutamoto T, et al. Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation. 2003;107(20):2555–8.

    Article  PubMed  Google Scholar 

  68. Balcells E, Meng QC, Johnson Jr WH, et al. Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol. 1997;273(4 Pt 2):H1769–74.

    CAS  PubMed  Google Scholar 

  69. Pat B, Chen Y, Killingsworth C, et al. Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation. Circulation. 2010;122(15):1488–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Wei CC, Meng QC, Palmer R, et al. Evidence for angiotensin-converting enzyme- and chymase-mediated angiotensin II formation in the interstitial fluid space of the dog heart in vivo. Circulation. 1999;99(19):2583–9.

    Article  CAS  PubMed  Google Scholar 

  71. Wei CC, Lucchesi PA, Tallaj J, et al. Cardiac interstitial bradykinin and mast cells modulate pattern of LV remodeling in volume overload in rats. Am J Physiol Heart Circ Physiol. 2003;285(2):H784–92.

    CAS  PubMed  Google Scholar 

  72. Wei CC, Chen Y, Powell LC, et al. Cardiac kallikrein-kinin system is upregulated in chronic volume overload and mediates an inflammatory induced collagen loss. PLoS One. 2012;7(6):e40110. Treatment of left heart valve insufficiency that leads to cardiac volume overload remains a formidable issue for which effective treatments are not available. In an experimental model of pure volume overload induced by the creation of an aorto-caval fistula, the authors demonstrate a significant contribution of the cardiac cellular kallikrein-kinin system and beneficial effects of blockade with aprotinin.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Wang H, Jessup JA, Zhao Z, et al. Characterization of the cardiac renin angiotensin system in oophorectomized and estrogen-replete mRen2.Lewis rats. PLoS One. 2013;8(10):e76992. By exploring the role of estrogen on the cardiac renin angiotensin system, the authors demonstrate a beneficial action of this sex steroid in blocking cardiac chymase Ang II formation.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Zhao Z, Wang H, Jessup JA et al. The Role of Estrogen in Diastolic Dysfunction. Am J Physiol Heart Circ Physiol 2014;306:H628–H640.

    Google Scholar 

  75. Dell'Italia LJ, Meng QC, Balcells E, et al. Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest. 1997;100(2):253–8.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Dell'Italia LJ, Husain A. Dissecting the role of chymase in angiotensin II formation and heart and blood vessel diseases. Curr Opin Cardiol. 2002;17(4):374–9.

    Article  PubMed  Google Scholar 

  77. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol. 1992;54:227–41.

    Article  CAS  PubMed  Google Scholar 

  78. Takai S, Sakaguchi M, Jin D, et al. Different angiotensin II-forming pathways in human and rat vascular tissues. Clin Chim Acta. 2001;305(1–2):191–5.

    Article  CAS  PubMed  Google Scholar 

  79. Raymond WW, Su S, Makarova A, et al. Alpha 2-macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity. J Immunol. 2009;182(9):5770–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Ferrario CM, Varagic J, Habibi J, et al. Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy. Am J Physiol Heart Circ Physiol. 2009;296(4):H1184–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Trask AJ, Jessup JA, Chappell MC, et al. Angiotensin-(1-12) is an alternate substrate for angiotensin peptide production in the heart. Am J Physiol Heart Circ Physiol. 2008;294(5):H2242–7.

    Article  CAS  PubMed  Google Scholar 

  82. Baker KM, Kumar R. Intracellular angiotensin II induces cell proliferation independent of AT1 receptor. Am J Physiol Cell Physiol. 2006;291(5):C995–1001.

    Article  CAS  PubMed  Google Scholar 

  83. Dell'Italia LJ, Balcells E, Meng QC, et al. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol. 1997;273(2 Pt 2):H961–70.

    PubMed  Google Scholar 

  84. Singh VP, Baker KM, Kumar R. Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol. 2008;294(4):H1675–84.

    Article  CAS  PubMed  Google Scholar 

  85. Gondo M, Maruta H, Arakawa K. Direct formation of angiotensin II without renin or converting enzyme in the ischemic dog heart. Jpn Heart J. 1989;30(2):219–29.

    Article  CAS  PubMed  Google Scholar 

  86. Ikeda M, Sasaguri M, Maruta H, et al. Formation of angiotensin II by tonin-inhibitor complex. Hypertension. 1988;11(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  87. Wintroub BU, Klickstein LB, Kaempfer CE, et al. A human neutrophil-dependent pathway for generation of angiotensin II: purification and physicochemical characterization of the plasma protein substrate. Proc Natl Acad Sci U S A. 1981;78(2):1204–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Wintroub BU, Klickstein LB, Dzau VJ, et al. Granulocyte-angiotensin system. Identification of angiotensinogen as the plasma protein substrate of leukocyte cathepsin G. Biochemistry. 1984;23(2):227–32.

    Article  CAS  PubMed  Google Scholar 

  89. Bujak-Gizycka B, Olszanecki R, Suski M, et al. Angiotensinogen metabolism in rat aorta: robust formation of proangiotensin-12. J Physiol Pharmacol. 2010;61(6):679–82.

    CAS  PubMed  Google Scholar 

  90. Simington SW, Moniwa N, Ahmad S, VonCannon J, Dell Italia LJ, Varagic J, et al. Renin does not participate in the production of plasma angiotensin-(1-12) from angiotensinogen. Hypertension. 2012;60:A628.

    Google Scholar 

  91. Arakawa K, Ikeda M, Fukuyama J, et al. A pressor formation by trypsin from renin-denatured human plasma protein. J Clin Endocrinol Metab. 1976;42(3):599–602.

    Article  CAS  PubMed  Google Scholar 

  92. Arakawa K, Maruta H. Ability of kallikrein to generate angiotensin II-like pressor substance and a proposed 'kinin-tensin enzyme system'. Nature. 1980;288(5792):705–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Sarfaraz Ahmad, Jasmina Varagic, Sayaka Nagata, Louis Dell'Italia and Neal Kon declare that they have no conflict of interest.

Leanne Groban and Carlos M. Ferrario have declared that this work was supported by grants HL-051952 from the National Heart, Lung and Blood Institute and AG042758 (LG) and AG033727 (LG) from the National Institute on Aging of the NIH.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Division of Surgical Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA

    Sarfaraz Ahmad, Jasmina Varagic, Sayaka Nagata & Carlos M. Ferrario

  2. Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA

    Jasmina Varagic & Leanne Groban

  3. Department of Physiology/Pharmacology, Wake Forest School of Medicine, Winston Salem, NC, USA

    Jasmina Varagic & Carlos M. Ferrario

  4. Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, NC, USA

    Leanne Groban

  5. Cardiothoracic Surgery, Wake Forest School of Medicine, Winston Salem, NC, USA

    Neal D. Kon

  6. Department of Internal Medicine/Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston Salem, NC, 27157, USA

    Carlos M. Ferrario

  7. Division of Cardiovascular Disease, Department of Medicine, University of Alabama Medical Center and Birmingham VA Medical Center, Birmingham, AL, USA

    Louis J Dell’Italia

Authors
  1. Sarfaraz Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jasmina Varagic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leanne Groban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louis J Dell’Italia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sayaka Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Neal D. Kon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos M. Ferrario
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos M. Ferrario.

Additional information

This article is part of the Topical Collection on Hypertension and the Kidney

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmad, S., Varagic, J., Groban, L. et al. Angiotensin-(1-12): A Chymase-Mediated Cellular Angiotensin II Substrate. Curr Hypertens Rep 16, 429 (2014). https://doi.org/10.1007/s11906-014-0429-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-014-0429-9

Keywords

Search

Navigation