Advertisement

Role of Chymase in Matrix and Myocardial Remodeling Due to Mitral Regurgitation: Implications for Therapy

  • Spencer J. Melby
  • Carlos M. Ferrario
  • Chih-Cheng Wei
  • Louis J. Dell’Italia
Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 5)

Abstract

The pure volume overload of mitral regurgitation (MR) has many unique features including matrix metalloproteinase (MMP) activation, increased bradykinin, extracellular matrix loss, disruption of the focal adhesion complex, and cardiomyocyte myofibrillar loss—all of which either directly or indirectly are beneficially affected by inhibition of chymase. Cardiomyocyte myofibrillar loss and cytoskeletal disruption may be related to intracellular oxidative stress and/or increased chymase production within the cardiomyocyte. Increased adrenergic drive is also an important underlying pathophysiologic feature, which, like chymase activation, is present both early and late in course of MR. There is now both dog and human data ­demonstrating the benefit of β1-receptor blockade in isolated MR. However, neither ­chymase inhibition nor β1-receptor blockade alone attenuates left ventricular (LV) dilatation. These data raise the intriguing question whether the combination of a chymase inhibitor and β1-receptor blocker would have a synergistic effect in preventing LV remodeling, especially if started early in the course of isolated MR.

Keywords

Mitral regurgitation Volume overload Chymase Matrix metalloproteinase Focal adhesion kinase 

Notes

Acknowledgments

This study is supported by the Office of Research and Development, Medical Service, Department of Veteran Affairs (LJD), and Specialized Centers of Clinically Orientated Research grant in Cardiac Dysfunction P50HL077100 and in part by Teijin Pharmaceuticals Ltd, Tokyo, Japan (LJD).

References

  1. 1.
    Borer JS, Bonow RO (2003) Contemporary approach to aortic and mitral regurgitation. Circulation 108:2432–2438PubMedCrossRefGoogle Scholar
  2. 2.
    Bonow RO, Carabello BA, Chatterjee K et al (2006) ACC/AHA/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 3:e1–e148CrossRefGoogle Scholar
  3. 3.
    Dell’Italia LJ, Balcells E, Meng QC et al (1997) Volume overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in the dog. Am J Physiol Heart Circ Physiol 273:H961–H970Google Scholar
  4. 4.
    Perry GJ, Wei CC, Hankes GH et al (2002) Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog. JACC 39:1374–1379PubMedCrossRefGoogle Scholar
  5. 5.
    Ryan TD, Rothstein E, Aban I et al (2007) Left ventricular eccentric remodeling is mediated by bradykinin and precedes myocyte elongation in rats with volume overload. J Am Coll Cardiol 49:811–821PubMedCrossRefGoogle Scholar
  6. 6.
    Wei CC, Chen Y-W, Shi K et al (2012) Cardiac kallikrein kinin system is upregulated in chronic volume overload and mediates inflammatory induced collagen loss. PLoS One 7:e40110–e40113PubMedCrossRefGoogle Scholar
  7. 7.
    Zheng J, Chen Y, Pat B et al (2009) Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog. Circulation 119:2086–2095PubMedCrossRefGoogle Scholar
  8. 8.
    Chen Y-W, Pat B, Zheng J et al (2010) Tumor necrosis factor-α produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload. J Mol Cell Cardiol 49:70–78PubMedCrossRefGoogle Scholar
  9. 9.
    Chen Y, Pat B, Gladden JD, Zheng J et al (2011) Dynamic molecular and histopathological changes in inflammation and extracellular matrix turnover in the transition to heart failure in isolated volume overload. Am J Physiol Heart Circ Physiol 300:H2251–H2260PubMedCrossRefGoogle Scholar
  10. 10.
    Urabe Y, Mann DL, Kent RL et al (1992) Cellular and ventricular contractile dysfunction in experimental canine mitral regurgitation. Circ Res 70:131–147PubMedCrossRefGoogle Scholar
  11. 11.
    Schiros CG, Dell’Italia LJ, Gladden JD et al (2012) Magnetic resonance imaging with three-dimensional analysis reveals important left ventricular remodeling in isolated mitral regurgitation: implications beyond dimensions. Circulation 125:2334–2342PubMedCrossRefGoogle Scholar
  12. 12.
    Sabri A, Rafiq K, Kolpakov MA et al (2008) Impaired focal adhesion signaling in the course of volume overload due to mitral regurgitation in the dog. Effect of Beta-1 Adrenergic Receptor Blockade. Circ Res 102:1127–1136PubMedCrossRefGoogle Scholar
  13. 13.
    Samuel JL, Barrieux A, Dufour S et al (1991) Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 88:1737–1746PubMedCrossRefGoogle Scholar
  14. 14.
    Peng X, Kraus MS, Wei H et al (2006) Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J Clin Invest 116:217–227PubMedCrossRefGoogle Scholar
  15. 15.
    Ulasova E, Gladden JD, Zheng J et al (2010) Extracellular matrix loss in acute volume overload causes structural alterations and dysfunction in cardiomyocyte subsarcolemmal mitochondria. J Mol Cell Cardiol 50:147–156PubMedCrossRefGoogle Scholar
  16. 16.
    Nagatsu M, Zile MR, Tsutsui H et al (1994) Native β-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function. Circulation 89:818–826PubMedCrossRefGoogle Scholar
  17. 17.
    Hankes GH, Ardell JL, Tallaj J et al (2006) Beta1-adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog. Am J Physiol Heart Circ Physiol 291:H147–H151PubMedCrossRefGoogle Scholar
  18. 18.
    Mehta RH, Supiano MA, Oral H et al (2003) Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation. Am Heart J 145:1078–1085PubMedCrossRefGoogle Scholar
  19. 19.
    Mann DL, Kent RL, Parsons B, Cooper G (1992) Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 85:790–804PubMedCrossRefGoogle Scholar
  20. 20.
    Pat B, Killingsworth C, Denney T et al (2008) Dissociation between cardiomyocyte function and remodeling with β-adrenergic receptor blockade in isolated canine mitral regurgitation. Am J Physiol Heart Circ Physiol 295:H2321–H2327PubMedCrossRefGoogle Scholar
  21. 21.
    Tsutsui H, Spinale FG, Nagatsu M et al (1994) Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest 93:2639–2648PubMedCrossRefGoogle Scholar
  22. 22.
    Ahmed MI, Aban I, Lloyd SG et al (2012) A randomized controlled trial of Beta-1 receptor blockade in isolated degenerative mitral regurgitation. J Am Coll Cardiol 60(9):833–838PubMedCrossRefGoogle Scholar
  23. 23.
    Kolpakov MA, Seqqat R, Rafiq K et al (2009) Pleiotropic effects of neutrophils on myocyte apoptosis and left ventricular remodeling during early volume overload. J Mol Cell Cardiol 47:634–645PubMedCrossRefGoogle Scholar
  24. 24.
    Pat B, Killingsworth C, Denney T et al (2010) Mast cell stabilizer worsens left ventricular function and cardiomyocyte function and calcium homeostasis in dogs with isolated mitral regurgitation. J Card Fail 16:769–777PubMedCrossRefGoogle Scholar
  25. 25.
    Spinale FG, Coker ML, Krombach SR et al (1999) Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circ Res 85:364–376PubMedCrossRefGoogle Scholar
  26. 26.
    Stewart JA, Wei C-C, Brower GL et al (2003) Cardiac mast cell and chymase mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog. J Mol Cell Cardiol 35:311–319PubMedCrossRefGoogle Scholar
  27. 27.
    Dell’Italia LJ, Meng QC, Balcells E et al (1995) Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation. Am J Physiol Heart Circ Physiol 269:H2065–H2071Google Scholar
  28. 28.
    Urata H, Kinoshita A, Misono KS et al (1990) Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem 265:22348–22357PubMedGoogle Scholar
  29. 29.
    Urata H, Healy B, Stewart RW et al (1990) Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 66:883–890PubMedCrossRefGoogle Scholar
  30. 30.
    Chandrasekharan UM, Sanker S, Glynias MJ et al (1996) Angiotensin II-forming activity in a reconstructed ancestral chymase. Science 271:502–505PubMedCrossRefGoogle Scholar
  31. 31.
    Kakizoe E, Shiota N, Tanabe Y et al (2001) Isoform-selective upregulation of mast cell chymase in the development of skin fibrosis in scleroderma model mice. J Invest Dermatol 16:118–123CrossRefGoogle Scholar
  32. 32.
    Li M, Liu K, Michalicek J, Angus JA et al (2004) Involvement of chymase-mediated angiotensin II generation in blood pressure regulation. J Clin Invest 114:112–120PubMedGoogle Scholar
  33. 33.
    Wei CC, Hase N, Inoue Y et al (2010) Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest 120:1229–1239PubMedCrossRefGoogle Scholar
  34. 34.
    Fang KC, Raymond WW, Blount JL, Caughey GH (1997) Dog mast cell alpha-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem 272:25628–25635PubMedCrossRefGoogle Scholar
  35. 35.
    Tchougounova E, Lundequist A, Fajardo I et al (2005) A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 280:9291–9296PubMedCrossRefGoogle Scholar
  36. 36.
    Okumura K, Takai S, Muramatsu M et al (2004) Human chymase degrades human fibronectin. Clin Chim Acta 347:223–2235PubMedCrossRefGoogle Scholar
  37. 37.
    Forteza R, Lauredo I, Abraham WM, Conner GE (1999) Bronchial tissue kallikrein activity is regulated by hyaluronic acid binding. Am J Respir Cell Mol Biol 21:666–674PubMedGoogle Scholar
  38. 38.
    Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT (2003) Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 23:238–243PubMedCrossRefGoogle Scholar
  39. 39.
    Hara M, Ono K, Hwang MW, Iwasaki A et al (2002) Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med 195:375–381PubMedCrossRefGoogle Scholar
  40. 40.
    Caughey GH (2007) Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev 217:141–154PubMedCrossRefGoogle Scholar
  41. 41.
    Nagata S, Kato J, Sasaki K et al (2006) Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system. Biochem Biophys Res Commun 350:1026–1031PubMedCrossRefGoogle Scholar
  42. 42.
    Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM (2008) Localization of the novel angiotensin peptide, angiotensin-(1-12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol 294:H2614–H2618PubMedCrossRefGoogle Scholar
  43. 43.
    Trask AJ, Jessup JA, Chappell MC, Ferrario CM (2008) Angiotensin-(1-12) is an alternate substrate for angiotensin peptide production in the heart. Am J Physiol Heart Circ Physiol 294:H2242–H2247PubMedCrossRefGoogle Scholar
  44. 44.
    Ferrario C, Varagic J, Hanini J et al (2009) Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy. Am J Physiol Heart Circ Physiol 296:H1184–H1192PubMedCrossRefGoogle Scholar
  45. 45.
    Prosser HC, Forster ME, Richards AM, Pemberton CJ (2009) Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics. Cardiovasc Res 82:40–50PubMedCrossRefGoogle Scholar
  46. 46.
    Ahmad S, Simmons T, Varagic J et al (2011) Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue (2011). PLoS One 6:e28501PubMedCrossRefGoogle Scholar
  47. 47.
    Dell’Italia LJ, Meng QC, Balcells E et al (1997) Compartmentalization of angiotensin II ­generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest 100:253–258PubMedCrossRefGoogle Scholar
  48. 48.
    Hoshino F, Urata H, Inoue Y et al (2003) Chymase inhibitor improves survival in hamsters with myocardial infarction. J Cardiovasc Pharmacol 41(Suppl 1):S11–S18PubMedGoogle Scholar
  49. 49.
    Ihara M, Urata H, Shirai K et al (2003) High cardiac angiotensin-II-forming activity in infarcted and non-infarcted human myocardium. Cardiology 94:247–253CrossRefGoogle Scholar
  50. 50.
    Ihara M, Urata H, Kinoshita A et al (1999) Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension 33:1399–1405PubMedCrossRefGoogle Scholar
  51. 51.
    Arakawa K, Urata H (2000) Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension 36:638–641PubMedCrossRefGoogle Scholar
  52. 52.
    Uehara Y, Urata H, Sasaguri M et al (2000) Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. Hypertension 35:55–60PubMedCrossRefGoogle Scholar
  53. 53.
    Uehara Y, Urata H, Ideishi M et al (2002) Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta. Cardiovasc Res 55:870–876PubMedCrossRefGoogle Scholar
  54. 54.
    Swedenborg J, Mäyränpää MI, Kovanen PT (2011) Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 31:734–740PubMedCrossRefGoogle Scholar
  55. 55.
    Rafiq K, Sherajee SJ, Fan YY et al (2011) Blood glucose level and survival in streptozotocin-treated human chymase transgenic mice. Chin J Physiol 54:30–35PubMedCrossRefGoogle Scholar
  56. 56.
    Singh VP, Le B, Bhat VB et al (2007) High glucose induced regulation of intracellular angiotensin II synthesis and nuclear redistribution in cardiac myocytes. Am J Physiol Heart Circ Physiol 293:H939–H948PubMedCrossRefGoogle Scholar
  57. 57.
    Singh VP, Baker KM, Kumar R (2008) Activation of the intracellular renin angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol 294:H1675–H1684PubMedCrossRefGoogle Scholar
  58. 58.
    Lavrentyev EN, Estes AM, Malik KU et al (2007) Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res 101:455–464PubMedCrossRefGoogle Scholar
  59. 59.
    Koka V, Wang W, Huang XR et al (2006) Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications. Circulation 113:1353–1360PubMedCrossRefGoogle Scholar
  60. 60.
    Tsai CT, Lai LP, Hwang JJ et al (2008) Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation. J Hypertens 26:570–582PubMedCrossRefGoogle Scholar
  61. 61.
    Matsumoto T, Wada A, Tsutamoto T et al (2003) Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 107:2555–2558PubMedCrossRefGoogle Scholar
  62. 62.
    Jin D, Takai S, Sakaguchi M et al (2004) An antiarrhythmic effect of a chymase inhibitor after myocardial infarction. J Pharmacol Exp Ther 309:490–497PubMedCrossRefGoogle Scholar
  63. 63.
    Jin D, Takai S, Yamada M et al (2003) Impact of chymase inhibitor on cardiac function and survival after myocardial infarction. Cardiovasc Res 60:413–420PubMedCrossRefGoogle Scholar
  64. 64.
    Matsumoto C, Hayashi T, Kitada K et al (2009) Chymase plays an important role in left ventricular remodeling influenced by intermittent hypoxia in mice. Hypertension 54:164–171PubMedCrossRefGoogle Scholar
  65. 65.
    Oyamada S, Bianchi C, Takai S et al (2011) Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. J Pharmacol Exp Ther 339:143–151PubMedCrossRefGoogle Scholar
  66. 66.
    Pat B, Chen Y, Killingsworth C et al (2011) Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation. Circulation 122:1488–1495CrossRefGoogle Scholar
  67. 67.
    Fukuda N, Granzier HL, Ishiwata S, Kurihara S (2008) Physiological functions of the giant elastic protein titin in mammalian striated muscle. J Physiol Sci 58:151–159PubMedCrossRefGoogle Scholar
  68. 68.
    Bell SP, Nyland L, Tischler MD et al (2000) Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 87:235–240PubMedCrossRefGoogle Scholar
  69. 69.
    Warren CM, Joradan MC, Roos KP et al (2003) Titin isoform expression in normal and ­hypertensive myocardium. Cardiovasc Res 59:86–94PubMedCrossRefGoogle Scholar
  70. 70.
    Williams L, Howell N, Pagano D, Andreka P, Vertesaljai M, Pecor T, Frenneaux M, Granzier H (2009) Titin isoform expression in aortic stenosis. Clin Sci (Lond) 117:237–242CrossRefGoogle Scholar
  71. 71.
    Kruger M, Linkwa (2009) Titin-based mechanical signaling in normal and failing myocardium. J Mol Cell Cardiol 46:490–498CrossRefGoogle Scholar
  72. 72.
    Russel IK, Gotte MJW, Bronzwaer JG et al (2009) Left ventricular torsion. JACC Cardiovasc Imaging 2:648–655PubMedCrossRefGoogle Scholar
  73. 73.
    Dong S-J, Hees PS, Huang W-M et al (1999) Independent effects of preload, afterload and contractility on left ventricular torsion. Am J Physiol Heart Circ Physiol 277:H1053–H1060Google Scholar
  74. 74.
    Kim NN, Villegas S, Summerour SR, Villarreal FJ (1999) Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol 31:457–466PubMedCrossRefGoogle Scholar
  75. 75.
    Pawluczyk IZ, Tan EK, Lodwick D, Harris KP (2008) Kallikrein gene ‘knock-down’ by small interfering RNA transfection induces a profibrotic phenotype in rat mesangial cells. J Hypertens 26:93–101PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Spencer J. Melby
    • 1
    • 2
    • 3
  • Carlos M. Ferrario
    • 4
  • Chih-Cheng Wei
    • 5
    • 3
  • Louis J. Dell’Italia
    • 5
  1. 1.Birmingham Veteran Affairs Medical Center, University of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Cardiovascular SurgeryUniversity of Alabama Medical CenterAlabamaUSA
  3. 3.UAB Comprehensive Cardiovascular CenterUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Wake Forest University School of MedicineWinston-SalemUSA
  5. 5.Division of Cardiovascular Disease, Department of MedicineBirmingham Veteran Affairs Medical Center, University of Alabama at BirminghamBirminghamUSA

Personalised recommendations