Skip to main content
SpringerLink
Log in
Book cover

The Renin Angiotensin System in Cardiovascular Disease pp 159–172Cite as

A Ying-Yang Perspective on the Renin Angiotensin System in Cardiovascular Disease

  • Chapter
  • First Online:

  • 440 Accesses

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 24))

Abstract

The renin angiotensin system (RAS) plays a critical role in the regulation of the homeostatic control of arterial pressure, body fluids, and cardiovascular adjustments to metabolic needs. Angiotensin II (Ang II) is considered to be the main effector molecule of the RAS contributing to the adverse cardiac, vascular, and renal organ remodeling in the development and progression of the cardiovascular disease (CVD) through the activation of specific Ang II type 1 receptor (AT1R). The endocrine action of circulating Ang II in blood pressure regulation have been extensively documented. The biochemical pathways leading to the generation of the biologically active angiotensins result from the metabolic processing of angiotensinogen, a 425 amino acid protein synthetized primarily by the liver. According to the classical pathway, Ang II is generated by sequential cleavage of angiotensinogen to angiotensin I (Ang I) by renal renin. Ang I is then cleaved into Ang II primarily by angiotensin converting enzyme (ACE) in circulation and by chymase in the tissues. The complexity of biochemical cascade leading to the production of Ang II, the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)], and other biologically active peptides has now been expanded by the identification of shorter forms of the angiotensinogen substrate that upstream of Ang I are processed by non-renin dependent mechanisms. This chapter will detail the biochemical physiology of angiotensin-(1-12) [Ang-(1-12)] and its function as an endogenous source for Ang II generation. Collectively, the discovery of Ang-(1-12) offers an opportunity to unravel how intracellular synthesis of angiotensins proceeds through different biochemical mechanisms.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Fountain JH, Lappin SL (2022) Physiology, renin angiotensin system. StatPearls. Treasure Island (FL)

    Google Scholar 

  2. Olvera Lopez E, Ballard BD, Jan A (2022) Cardiovascular disease. StatPearls. Treasure Island (FL)

    Google Scholar 

  3. Atlas SA (2007) The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 13(8 Suppl B):9–20

    Google Scholar 

  4. Vargas F, Rodriguez-Gomez I, Vargas-Tendero P, Jimenez E, Montiel M (2012) The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations. J Endocrinol 213(1):25–36

    Article  CAS  Google Scholar 

  5. Lavoie JL, Sigmund CD (2003) Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology 144(6):2179–2183

    Article  CAS  Google Scholar 

  6. Carey RM (2013) Newly discovered components and actions of the renin-angiotensin system. Hypertension 62(5):818–822

    Article  CAS  Google Scholar 

  7. Ferrario CM (2006) Angiotensin-converting enzyme 2 and angiotensin-(1-7): an evolving story in cardiovascular regulation. Hypertension 47(3):515–521

    Article  CAS  Google Scholar 

  8. Ferrario CM, Trask AJ, Jessup JA (2005) 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 289(6):H2281-2290

    Article  CAS  Google Scholar 

  9. Nehme A, Zouein FA, Zayeri ZD, Zibara K (2019) An update on the tissue renin angiotensin system and its role in physiology and pathology. J Cardiovasc Dev Dis 6(2)

    Google Scholar 

  10. Crackower MA, Sarao R, Oudit GY et al (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417(6891):822–828

    Article  CAS  Google Scholar 

  11. Touyz RM, Montezano AC (2018) Angiotensin-(1-7) and vascular function: the clinical context. Hypertension 71(1):68–69

    Article  CAS  Google Scholar 

  12. Kaschina E, Namsolleck P, Unger T (2017) AT2 receptors in cardiovascular and renal diseases. Pharmacol Res 125(Pt A):39–47

    Article  CAS  Google Scholar 

  13. Pulakat L, Sumners C (2020) Angiotensin type 2 receptors: painful, or not? Front Pharmacol 11:571994

    Article  CAS  Google Scholar 

  14. Patel VB, Zhong JC, Grant MB, Oudit GY (2016) Role of the ACE2/Angiotensin 1–7 axis of the renin-angiotensin system in heart failure. Circ Res 118(8):1313–1326

    Article  CAS  Google Scholar 

  15. Xia H, Lazartigues E (2010) Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Curr Hypertens Rep 12(3):170–175

    Article  CAS  Google Scholar 

  16. Ferrario CM (2010) New physiological concepts of the renin-angiotensin system from the investigation of precursors and products of angiotensin I metabolism. Hypertension 55(2):445–452

    Article  CAS  Google Scholar 

  17. Sharma N, Anders HJ, Gaikwad AB (2019) Fiend and friend in the renin angiotensin system: an insight on acute kidney injury. Biomed Pharmacother 110:764–774

    Article  CAS  Google Scholar 

  18. Mao C, Shi L, Li N, Xu F, Xu Z (2014) Development of local RAS in cardiovascular/body fluid regulatory systems and hypertension in fetal origins. In: De Luca Jr LA, Menani JV, Johnson AK (eds) Neurobiology of body fluid homeostasis: transduction and integration. Boca Raton (FL)

    Google Scholar 

  19. Ferrario CM (1990) Importance of the renin-angiotensin-aldosterone system (RAS) in the physiology and pathology of hypertension. An overview. Drugs 39(Suppl 2):1–8

    Article  Google Scholar 

  20. Ferrario CM (1990) The renin-angiotensin system: importance in physiology and pathology. J Cardiovasc Pharmacol 15(Suppl 3):S1-5

    Article  Google Scholar 

  21. Danser AH, Saris JJ, Schuijt MP, van Kats JP (1999) Is there a local renin-angiotensin system in the heart? Cardiovasc Res 44(2):252–265

    Article  CAS  Google Scholar 

  22. Arnold AC, Isa K, Shaltout HA et al (2010) Angiotensin-(1-12) requires angiotensin converting enzyme and AT1 receptors for cardiovascular actions within the solitary tract nucleus. Am J Physiol Heart Circ Physiol 299(3):H763-771

    Article  CAS  Google Scholar 

  23. Savoia C, Arrabito E, Parente R et al (2020) Mas receptor activation contributes to the improvement of nitric oxide bioavailability and vascular remodeling during chronic AT1R (angiotensin type-1 receptor) blockade in experimental hypertension. Hypertension 76(6):1753–1761

    Article  CAS  Google Scholar 

  24. Paz Ocaranza M, Riquelme JA, Garcia L et al (2020) Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 17(2):116–129

    Article  Google Scholar 

  25. Li Y, Li XH, Yuan H (2012) Angiotensin II type-2 receptor-specific effects on the cardiovascular system. Cardiovasc Diagn Ther 2(1):56–62

    Google Scholar 

  26. Matsubara H (1998) Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res 83(12):1182–1191

    Article  CAS  Google Scholar 

  27. Hirose T, Mori N, Totsune K et al (2009) Gene expression of (pro)renin receptor is upregulated in hearts and kidneys of rats with congestive heart failure. Peptides 30(12):2316–2322

    Article  CAS  Google Scholar 

  28. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109(11):1417–1427

    Article  CAS  Google Scholar 

  29. Passier RC, Smits JF, Verluyten MJ, Daemen MJ (1996) Expression and localization of renin and angiotensinogen in rat heart after myocardial infarction. Am J Physiol 271(3 Pt 2):H1040-1048

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Ruiz-Ortega M, Lorenzo O, Ruperez M et al (2001) Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 38(6):1382–1387

    Article  CAS  Google Scholar 

  32. Raizada V, Skipper B, Luo W, Griffith J (2007) Intracardiac and intrarenal renin-angiotensin systems: mechanisms of cardiovascular and renal effects. J Investig Med 55(7):341–359

    Article  CAS  Google Scholar 

  33. Deshotels MR, Xia H, Sriramula S, Lazartigues E, Filipeanu CM (2014) Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension 64(6):1368–1375

    Article  CAS  Google Scholar 

  34. Ferrario CM, VonCannon J, Ahmad S et al (2019) Activation of the human angiotensin-(1-12)-chymase pathway in rats with human angiotensinogen gene transcripts. Front Cardiovasc Med. 6:163

    Article  CAS  Google Scholar 

  35. Dostal DE, Baker KM (1999) The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res 85(7):643–650

    Article  CAS  Google Scholar 

  36. Tamura K, Umemura S, Nyui N et al (1998) Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch. Am J Physiol 275(1):R1-9

    CAS  Google Scholar 

  37. Malhotra R, Sadoshima J, Brosius FC 3rd, Izumo S (1999) Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes In vitro. Circ Res 85(2):137–146

    Article  CAS  Google Scholar 

  38. De Mello WC, Danser AH (2000) Angiotensin II and the heart: on the intracrine renin-angiotensin system. Hypertension 35(6):1183–1188

    Article  Google Scholar 

  39. Ahmad S, Varagic J, Westwood BM, Chappell MC, Ferrario CM (2011) Uptake and metabolism of the novel peptide angiotensin-(1-12) by neonatal cardiac myocytes. PLoS ONE 6(1):e15759

    Article  CAS  Google Scholar 

  40. Li XC, Hopfer U, Zhuo JL (2009) AT1 receptor-mediated uptake of angiotensin II and NHE-3 expression in proximal tubule cells through a microtubule-dependent endocytic pathway. Am J Physiol Renal Physiol 297(5):F1342-1352

    Article  CAS  Google Scholar 

  41. Powell PC, Wei CC, Fu L et al (2019) Chymase uptake by cardiomyocytes results in myosin degradation in cardiac volume overload. Heliyon 5(4):e01397

    Article  Google Scholar 

  42. Gironacci MM, Adamo HP, Corradi G, Santos RA, Ortiz P, Carretero OA (2011) Angiotensin (1-7) induces MAS receptor internalization. Hypertension 58(2):176–181

    Article  CAS  Google Scholar 

  43. Inuzuka T, Fujioka Y, Tsuda M et al (2016) Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via protein kinase C. Sci Rep 6:21613

    Article  CAS  Google Scholar 

  44. Brown NJ, Vaughan DE (1998) Angiotensin-converting enzyme inhibitors. Circulation 97(14):1411–1420

    Article  CAS  Google Scholar 

  45. Beldent V, Michaud A, Wei L, Chauvet MT, Corvol P (1993) Proteolytic release of human angiotensin-converting enzyme. Localization of the cleavage site. J Biol Chem 268(35):26428–26434

    Google Scholar 

  46. Sanker S, Chandrasekharan UM, Wilk D, Glynias MJ, Karnik SS, Husain A (1997) Distinct multisite synergistic interactions determine substrate specificities of human chymase and rat chymase-1 for angiotensin II formation and degradation. J Biol Chem 272(5):2963–2968

    Article  CAS  Google Scholar 

  47. Duengen HD, Kim RJ, Zahger D et al (2020) Effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute myocardial infarction—Results of the Chymase Inhibitor in Adverse Remodeling after Myocardial Infarction (CHIARA MIA) 2 trial. Am Heart J 224:129–137

    Article  CAS  Google Scholar 

  48. Kanefendt F, Thuss U, Becka M et al (2019) Pharmacokinetics, safety, and tolerability of the novel chymase inhibitor BAY 1142524 in healthy male volunteers. Clin Pharmacol Drug Dev 8(4):467–479

    Article  CAS  Google Scholar 

  49. Arakawa K, Urata H (2000) Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension 36(4):638–641

    Article  CAS  Google Scholar 

  50. Dell’Italia LJ, Ferrario CM (2013) The never-ending story of angiotensin peptides: beyond angiotensin I and II. Circ Res 112(8):1086–1087

    Article  CAS  Google Scholar 

  51. Takai S, Jin D (2016) Improvement of cardiovascular remodelling by chymase inhibitor. Clin Exp Pharmacol Physiol 43(4):387–393

    Article  CAS  Google Scholar 

  52. Takai S, Jin D, Miyazaki M (2011) Targets of chymase inhibitors. Exp Opin Ther Targets 15(4):519–527

    Article  CAS  Google Scholar 

  53. Dungen HD, Kober L, Nodari S et al (2019) Safety and tolerability of the chymase inhibitor fulacimstat in patients with left ventricular dysfunction after myocardial infarction—results of the CHIARA MIA 1 trial. Clin Pharmacol Drug Dev. 8(7):942–951

    Article  Google Scholar 

  54. Rossing P, Strand J, Avogaro A, Becka M, Kanefendt F, Otto C (2021) Effects of the chymase inhibitor fulacimstat in diabetic kidney disease—results from the CADA DIA trial. Nephrol Dial Transplant 36(12):2263–2273

    Article  CAS  Google Scholar 

  55. Dell’Italia LJ, Collawn JF, Ferrario CM (2018) Multifunctional role of chymase in acute and chronic tissue injury and remodeling. Circ Res 122(2):319–336

    Article  CAS  Google Scholar 

  56. Lindstedt L, Lee M, Kovanen PT (2001) Chymase bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid. Atherosclerosis 155(1):87–97

    Article  CAS  Google Scholar 

  57. Raymond WW, Su S, Makarova A et al (2009) Alpha 2-macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity. J Immunol 182(9):5770–5777

    Article  CAS  Google Scholar 

  58. Walter M, Sutton RM, Schechter NM (1999) Highly efficient inhibition of human chymase by alpha(2)-macroglobulin. Arch Biochem Biophys 368(2):276–284

    Article  CAS  Google Scholar 

  59. He SH, Xie H, Zhang XJ, Wang XJ (2004) Inhibition of histamine release from human mast cells by natural chymase inhibitors. Acta Pharmacol Sin 25(6):822–826

    CAS  Google Scholar 

  60. Ahmad S, Simmons T, Varagic J, Moniwa N, Chappell MC, Ferrario CM (2011) Chymase-dependent generation of angiotensin II from angiotensin-(1–12) in human atrial tissue. PLoS ONE 6(12):e28501

    Article  CAS  Google Scholar 

  61. Ahmad S, Varagic J, Groban L et al (2014) Angiotensin-(1-12): a chymase-mediated cellular angiotensin II substrate. Curr Hypertens Rep 16(5):429

    Article  Google Scholar 

  62. Ahmad S, Varagic J, VonCannon JL et al (2016) Primacy of cardiac chymase over angiotensin converting enzyme as an angiotensin-(1-12) metabolizing enzyme. Biochem Biophys Res Commun 478(2):559–564

    Article  CAS  Google Scholar 

  63. Ahmad S, Wei CC, Tallaj J et al (2013) Chymase mediates angiotensin-(1-12) metabolism in normal human hearts. J Am Soc Hypertens 7(2):128–136

    Article  CAS  Google Scholar 

  64. Ferrario CM, Ahmad S, Nagata S et al (2014) An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond) 126(7):461–469

    Article  CAS  Google Scholar 

  65. Ferrario CM, Groban L, Wang H et al (2021) The Angiotensin-(1–12)/Chymase axis as an alternate component of the tissue renin angiotensin system. Mol Cell Endocrinol 529:111119

    Article  CAS  Google Scholar 

  66. Ahmad S, Wright KN, Sun X, Groban L, Ferrario CM (2019) Mast cell peptidases (carboxypeptidase A and chymase)-mediated hydrolysis of human angiotensin-(1-12) substrate. Biochem Biophys Res Commun 518(4):651–656

    Article  CAS  Google Scholar 

  67. Ahmad S, Ferrario CM (2018) Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018). Exp Opin Ther Pat 28(11):755–764

    Article  CAS  Google Scholar 

  68. Bacani C, Frishman WH (2006) Chymase: a new pharmacologic target in cardiovascular disease. Cardiol Rev 14(4):187–193

    Article  Google Scholar 

  69. Lagraauw HM, Wezel A, van der Velden D, Kuiper J, Bot I (2019) Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization. Sci Rep 9(1):2134

    Article  Google Scholar 

  70. Dikalov SI, Nazarewicz RR (2013) Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. Antioxid Redox Sig 19(10):1085–1094

    Article  CAS  Google Scholar 

  71. Virdis A, Duranti E, Taddei S (2011) Oxidative stress and vascular damage in hypertension: role of angiotensin II. Int J Hypertens 2011:916310

    Article  Google Scholar 

  72. Kucmierz J, Frak W, Mlynarska E, Franczyk B, Rysz J (2021) Molecular interactions of arterial hypertension in its target organs. Int J Mol Sci. 22(18)

    Google Scholar 

  73. Son A, Nakamura H, Kondo N et al (2006) Redox regulation of mast cell histamine release in thioredoxin-1 (TRX) transgenic mice. Cell Res 16(2):230–239

    Article  CAS  Google Scholar 

  74. Chelombitko MA, Fedorov AV, Ilyinskaya OP, Zinovkin RA, Chernyak BV (2016) Role of reactive oxygen species in mast cell degranulation. Biochemistry (Mosc) 81(12):1564–1577

    Article  CAS  Google Scholar 

  75. Suzuki Y, Yoshimaru T, Inoue T, Niide O, Ra C (2005) Role of oxidants in mast cell activation. Chem Immunol Allergy 87:32–42

    Article  CAS  Google Scholar 

  76. Pejler G (2020) Novel insight into the in vivo function of mast cell chymase: lessons from knockouts and inhibitors. J Innate Immun 12(5):357–372

    Article  CAS  Google Scholar 

  77. Yamashita T, Ahmad S, Wright KN et al (2020) Noncanonical mechanisms for direct bone marrow generating Ang II (Angiotensin II) predominate in CD68 positive myeloid lineage cells. Hypertension 75(2):500–509

    Article  CAS  Google Scholar 

  78. Dahlin JS, Hallgren J (2015) Mast cell progenitors: origin, development and migration to tissues. Mol Immunol 63(1):9–17

    Article  CAS  Google Scholar 

  79. Derakhshan T, Bhowmick R, Ritchey JW, Gappa-Fahlenkamp H (2018) Development of human mast cells from hematopoietic stem cells within a 3D collagen matrix: effect of stem cell media on mast cell generation. Stem Cells Int 2018:2136193

    Article  Google Scholar 

  80. Hermans M, Lennep JRV, van Daele P, Bot I (2019) Mast cells in cardiovascular disease: from bench to bedside. Int J Mol Sci 20(14)

    Google Scholar 

  81. Frangogiannis NG, Perrard JL, Mendoza LH et al (1998) Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion. Circulation 98(7):687–698

    Article  CAS  Google Scholar 

  82. Janicki JS, Brower GL, Levick SP (2015) The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling. Methods Mol Biol 1220:121–139

    Article  CAS  Google Scholar 

  83. Nagata S, Kato J, Sasaki K, Minamino N, Eto T, Kitamura K (2006) Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system. Biochem Biophys Res Commun 350(4):1026–1031

    Article  CAS  Google Scholar 

  84. Ferrario CM, Iyer SR, Burnett JC Jr et al (2021) Angiotensin (1-12) in humans with normal blood pressure and primary hypertension. Hypertension 77(3):882–890

    Article  CAS  Google Scholar 

  85. Ahmad S, Punzi HA, Wright KN, Groban L, Ferrario CM (2021) Newly developed radioimmunoassay for Human Angiotensin-(1–12) measurements in plasma and urine. Mol Cell Endocrinol 529:111256

    Article  CAS  Google Scholar 

  86. Moniwa N, Varagic J, Simington SW et al (2013) Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism. Am J Physiol Heart Circ Physiol 305(5):H644-650

    Article  CAS  Google Scholar 

  87. Ferrario CM (2016) Cardiac remodelling and RAS inhibition. Ther Adv Cardiovasc Dis 10(3):162–171

    Article  CAS  Google Scholar 

  88. Ferrario CM, Ahmad S, Varagic J et al (2016) Intracrine angiotensin II functions originate from noncanonical pathways in the human heart. Am J Physiol Heart Circ Physiol 311(2):H404-414

    Article  Google Scholar 

  89. Ferrario CM, Mullick AE (2017) Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res 125(Pt A):57–71

    Article  CAS  Google Scholar 

  90. Reyes S, Varagic J, Ahmad S et al (2017) Novel cardiac intracrine mechanisms based on Ang-(1–12)/chymase axis require a revision of therapeutic approaches in human heart disease. Curr Hypertens Rep 19(2):16

    Article  Google Scholar 

  91. Dusing R (2016) Mega clinical trials which have shaped the RAS intervention clinical practice. Ther Adv Cardiovasc Dis 10(3):133–150

    Article  Google Scholar 

  92. Dusing R (2016) Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering. Ther Adv Cardiovasc Dis 10(3):151–161

    Article  Google Scholar 

  93. Brugts JJ, van Vark L, Akkerhuis M et al (2015) Impact of renin-angiotensin system inhibitors on mortality and major cardiovascular endpoints in hypertension: a number-needed-to-treat analysis. Int J Cardiol 181:425–429

    Article  Google Scholar 

  94. van der Leeuw J, Oemrawsingh RM, van der Graaf Y et al (2015) Prediction of absolute risk reduction of cardiovascular events with perindopril for individual patients with stable coronary artery disease—results from EUROPA. Int J Cardiol 182:194–199

    Article  Google Scholar 

  95. Vanuzzo D (2011) The epidemiological concept of residual risk. Intern Emerg Med 6(Suppl 1):45–51

    Article  Google Scholar 

  96. Basu R, Poglitsch M, Yogasundaram H, Thomas J, Rowe BH, Oudit GY (2017) Roles of angiotensin peptides and recombinant human ACE2 in heart failure. J Am Coll Cardiol 69(7):805–819

    Article  CAS  Google Scholar 

  97. Hristova M, Stanilova S, Miteva L (2019) Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy. Clin Exp Hypertens 41(7):662–669

    Article  CAS  Google Scholar 

  98. Ennezat PV, Berlowitz M, Sonnenblick EH, Le Jemtel TH (2000) Therapeutic implications of escape from angiotensin-converting enzyme inhibition in patients with chronic heart failure. Curr Cardiol Rep 2(3):258–262

    Article  CAS  Google Scholar 

  99. Nagata S, Kato J, Kuwasako K, Asami M, Kitamura K (2012) Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system. Hypertens Res 35(2):234–238

    Article  CAS  Google Scholar 

  100. Nagata S, Kato J, Kuwasako K, Kitamura K (2010) Plasma and tissue levels of proangiotensin-12 and components of the renin-angiotensin system (RAS) following low- or high-salt feeding in rats. Peptides 31(5):889–892

    Article  CAS  Google Scholar 

  101. Balcells E, Meng QC, Hageman GR, Palmer RW, Durand JN, Dell’Italia LJ (1996) Angiotensin II formation in dog heart is mediated by different pathways in vivo and in vitro. Am J Physiol 271(2 Pt 2):H417-421

    CAS  Google Scholar 

  102. Balcells E, Meng QC, Johnson WH Jr, Oparil S, Dell’Italia LJ (1997) Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol 273(4):H1769-1774

    CAS  Google Scholar 

  103. Butts B, Goeddel LA, George DJ et al (2017) Increased inflammation in pericardial fluid persists 48 hours after cardiac surgery. Circulation 136(23):2284–2286

    Article  Google Scholar 

  104. Fu L, Wei CC, Powell PC et al (2016) Increased fibroblast chymase production mediates procollagen autophagic digestion in volume overload. J Mol Cell Cardiol 92:1–9

    Article  CAS  Google Scholar 

  105. Zheng J, Wei CC, Hase N et al (2014) Chymase mediates injury and mitochondrial damage in cardiomyocytes during acute ischemia/reperfusion in the dog. PLoS ONE 9(4):e94732

    Article  Google Scholar 

  106. Ferrario CM, VonCannon J, Jiao Y et al (2016) Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene. Am J Physiol Heart Circ Physiol 310(8):H995-1002

    Article  Google Scholar 

  107. Ola MS, Alhomida AS, Ferrario CM, Ahmad S (2017) Role of tissue renin-angiotensin system and the chymase/angiotensin-(1-12) axis in the pathogenesis of diabetic retinopathy. Curr Med Chem 24(28):3104–3114

    Article  CAS  Google Scholar 

  108. Reyes S, Cheng CP, Roberts DJ et al (2019) Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen. Int J Cardiol 297:104–110

    Article  Google Scholar 

  109. Wang H, Varagic J, Nagata S et al (2020) Differential expression of the angiotensin-(1-12)/chymase axis in human atrial tissue. J Surg Res 253:173–184

    Article  CAS  Google Scholar 

  110. Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrario CM (1998) Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan. Hypertension 31(2):699–705

    Article  CAS  Google Scholar 

  111. Jessup JA, Gallagher PE, Averill DB et al (2006) Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. Am J Physiol Heart Circ Physiol 291(5):H2166-2172

    Article  CAS  Google Scholar 

  112. Elgundi Z, Reslan M, Cruz E, Sifniotis V, Kayser V (2017) The state-of-play and future of antibody therapeutics. Adv Drug Deliv Rev 122:2–19

    Article  CAS  Google Scholar 

  113. Lu RM, Hwang YC, Liu IJ et al (2020) Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27(1):1

    Article  CAS  Google Scholar 

  114. Ridker PM (2017) Canakinumab for residual inflammatory risk. Eur Heart J 38(48):3545–3548

    Article  CAS  Google Scholar 

  115. Ridker PM (2018) Clinician’s guide to reducing inflammation to reduce atherothrombotic risk: JACC review topic of the week. J Am Coll Cardiol 72(25):3320–3331

    Article  Google Scholar 

  116. Ridker PM (2018) Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications. Circulation 137(17):1763–1766

    Article  Google Scholar 

  117. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131

    Article  CAS  Google Scholar 

  118. Ridker PM, Libby P, MacFadyen JG et al (2018) Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 39(38):3499–3507

    Article  CAS  Google Scholar 

  119. Ridker PM, Luscher TF (2014) Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 35(27):1782–1791

    Article  CAS  Google Scholar 

  120. Ferrario CM, VonCannon JL, Zhang J et al (2022) Immunoneutralization of human angiotensin-(1-12) with a monoclonal antibody in a humanized model of hypertension. Peptides 149:170714

    Article  CAS  Google Scholar 

  121. Jovcevska I, Muyldermans S (2020) The therapeutic potential of nanobodies. BioDrugs 34(1):11–26

    Article  CAS  Google Scholar 

  122. Yang EY, Shah K (2020) Nanobodies: next generation of cancer diagnostics and therapeutics. Front Oncol 10:1182

    Article  CAS  Google Scholar 

  123. Custodio TF, Das H, Sheward DJ et al (2020) Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat Commun 11(1):5588

    Article  CAS  Google Scholar 

  124. Martinez-Delgado G (2020) Inhaled nanobodies against COVID-19. Nat Rev Immunol 20(10):593

    Article  CAS  Google Scholar 

  125. Huo J, Le Bas A, Ruza RR et al (2020) Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat Struct Mol Biol 27(9):846–854

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, North Carolina, 27157, USA

    Sarfaraz Ahmad & Carlos M. Ferrario

Authors
  1. Sarfaraz Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos M. Ferrario
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarfaraz Ahmad .

Editor information

Editors and Affiliations

  1. Institute of Cardiovascular Sciences, St. Boniface Hospital, Manitoba, MB, Canada

    Naranjan S. Dhalla

  2. Institute of Cardiovascular Sciences, St. Boniface Hospital, Winnipeg, MB, Canada

    Sukhwinder K. Bhullar

  3. California State University Los Angeles, Los Angeles, CA, USA

    Anureet K. Shah

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ahmad, S., Ferrario, C.M. (2023). A Ying-Yang Perspective on the Renin Angiotensin System in Cardiovascular Disease. In: Dhalla, N.S., Bhullar, S.K., Shah, A.K. (eds) The Renin Angiotensin System in Cardiovascular Disease. Advances in Biochemistry in Health and Disease, vol 24. Springer, Cham. https://doi.org/10.1007/978-3-031-14952-8_10

Download citation

Publish with us

Policies and ethics

Search

Navigation