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An Emerging Role of Degrading Proteinases in Hypertension and the Metabolic Syndrome: Autodigestion and Receptor Cleavage

Current Hypertension Reports volume 14, pages 88–96 (2012)Cite this article

Abstract

One of the major challenges for hypertension research is to identify the mechanisms that cause the comorbidities encountered in many hypertensive patients, as seen in the metabolic syndrome. An emerging body of evidence suggests that human and experimental hypertensives may exhibit uncontrolled activity of proteinases, including the family of matrix metalloproteinases, recognized for their ability to restructure the extracellular matrix proteins and to play a role in hypertrophy. We propose a new hypothesis that provides a molecular framework for the comorbidities of hypertension, diabetes, capillary rarefaction, immune suppression, and other cell and organ dysfunctions due to early and uncontrolled extracellular receptor cleavage by active proteinases. The proteinase and signaling activity in hypertensives requires further detailed analysis of the proteinase expression, the mechanisms causing proenzyme activation, and identification of the proteinase substrate. This work may open the opportunity for reassessment of old interventions and development of new interventions to manage hypertension and its comorbidities.

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References

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

  1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–607.

    PubMed  Article  CAS  Google Scholar 

  2. Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 2010;41(2):271–90.

    PubMed  Article  Google Scholar 

  3. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002;90(3):251–62.

    PubMed  CAS  Google Scholar 

  4. Rodriguez JA, Orbe J, Martinez de Lizarrondo S, et al. Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli. Front Biosci. 2008;13:2916–21.

    PubMed  Article  CAS  Google Scholar 

  5. Ronco P, Lelongt B, Piedagnel R, Chatziantoniou C. Matrix metalloproteinases in kidney disease progression and repair: a case of flipping the coin. Semin Nephrol. 2007;27(3):352–62.

    PubMed  Article  CAS  Google Scholar 

  6. Thrailkill KM. Clay Bunn R, Fowlkes JL: Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy. Endocrine. 2009;35(1):1–10.

    PubMed  Article  CAS  Google Scholar 

  7. Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol. 2008;8(1):82–9.

    PubMed  Article  CAS  Google Scholar 

  8. Moore L, Fan D, Basu R, et al.: Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail Rev 2011 Jun 30 (Epub ahead of print).

  9. Turu MM, Krupinski J, Catena E, et al. Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound. Atherosclerosis. 2006;187(1):161–9.

    PubMed  Article  CAS  Google Scholar 

  10. Iwanaga Y, Aoyama T, Kihara Y, et al. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol. 2002;39(8):1384–91.

    PubMed  Article  CAS  Google Scholar 

  11. Shah BH, Catt KJ. Matrix metalloproteinase-dependent EGF receptor activation in hypertension and left ventricular hypertrophy. Trends Endocrinol Metab. 2004;15(6):241–3.

    PubMed  Article  CAS  Google Scholar 

  12. Tayebjee MH, MacFadyen RJ, Lip GY. Extracellular matrix biology: a new frontier in linking the pathology and therapy of hypertension? J Hypertens. 2003;21(12):2211–8.

    PubMed  Article  CAS  Google Scholar 

  13. Ammarguellat FZ, Gannon PO, Amiri F, Schiffrin EL. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: role of ET(A) receptors. Hypertension. 2002;39(2 Pt 2):679–84.

    PubMed  Article  CAS  Google Scholar 

  14. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90(5):520–30.

    PubMed  Article  CAS  Google Scholar 

  15. Barbour JR, Spinale FG, Ikonomidis JS. Proteinase systems and thoracic aortic aneurysm progression. J Surg Res. 2007;139(2):292–307.

    PubMed  Article  CAS  Google Scholar 

  16. Kaneko H, Anzai T, Horiuchi K, et al. Tumor necrosis factor-alpha converting enzyme is a key mediator of abdominal aortic aneurysm development. Atherosclerosis. 2011;218(2):470–8.

    PubMed  Article  CAS  Google Scholar 

  17. Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001;38(3 Pt 2):581–7.

    PubMed  Article  CAS  Google Scholar 

  18. Raffetto JD, Khalil RA. Matrix metalloproteinases in venous tissue remodeling and varicose vein formation. Curr Vasc Pharmacol. 2008;6(3):158–72.

    PubMed  Article  CAS  Google Scholar 

  19. Lehoux S, Lemarie CA, Esposito B, et al. Pressure-induced matrix metalloproteinase-9 contributes to early hypertensive remodeling. Circulation. 2004;109(8):1041–7.

    PubMed  Article  CAS  Google Scholar 

  20. Spiers JP, Kelso EJ, Siah WF, et al. Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension: effects of endothelin receptor blockade. J Hypertens. 2005;23(9):1717–24.

    PubMed  Article  CAS  Google Scholar 

  21. Mujumdar VS, Smiley LM, Tyagi SC. Activation of matrix metalloproteinase dilates and decreases cardiac tensile strength. Int J Cardiol. 2001;79(2–3):277–86.

    PubMed  Article  CAS  Google Scholar 

  22. Ergul A, Portik-Dobos V, Giulumian AD, et al. Stress upregulates arterial matrix metalloproteinase expression and activity via endothelin A receptor activation. Am J Physiol Heart Circ Physiol. 2003;285(5):H2225–2232.

    PubMed  CAS  Google Scholar 

  23. Bouvet C, Gilbert LA, Girardot D, et al. Different involvement of extracellular matrix components in small and large arteries during chronic NO synthase inhibition. Hypertension. 2005;45(3):432–7.

    PubMed  Article  CAS  Google Scholar 

  24. Seccia TM, Bettini E, Vulpis V, et al. Extracellular matrix gene expression in the left ventricular tissue of spontaneously hypertensive rats. Blood Press. 1999;8(1):57–64.

    PubMed  Article  CAS  Google Scholar 

  25. Shinzato T, Ohya Y, Nakamoto M, et al. Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats. Hypertens Res. 2007;30(9):863–73.

    PubMed  Article  CAS  Google Scholar 

  26. Rodriguez WE, Tyagi N, Deng AY, et al. Congenic expression of tissue inhibitor of metalloproteinase in Dahl-salt sensitive hypertensive rats is associated with reduced LV hypertrophy. Arch Physiol Biochem. 2008;114(5):340–8.

    PubMed  Article  CAS  Google Scholar 

  27. Haas TL, Doyle JL, Distasi MR, et al. Involvement of MMPs in the outward remodeling of collateral mesenteric arteries. Am J Physiol Heart Circ Physiol. 2007;293(4):H2429–2437.

    PubMed  Article  CAS  Google Scholar 

  28. Dumont O, Loufrani L, Henrion D. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler Thromb Vasc Biol. 2007;27(2):317–24.

    PubMed  Article  CAS  Google Scholar 

  29. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest. 2000;105(1):21–34.

    PubMed  Article  CAS  Google Scholar 

  30. Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008;75(2):346–59.

    PubMed  Article  CAS  Google Scholar 

  31. • Wang X, Chow FL, Oka T, et al.: Matrix metalloproteinase-7 and ADAM-12 (a disintegrin and metalloproteinase-12) define a signaling axis in agonist-induced hypertension and cardiac hypertrophy. Circulation 2009;119(18):2480–2489. This article demonstrates that hypertension and hypertrophy depend on transcriptional and posttranscriptional mechanisms involving MMP-7 and transcriptional connection with ADAM-12.

    PubMed  Article  CAS  Google Scholar 

  32. Prenzel N, Zwick E, Daub H, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999;402(6764):884–8.

    PubMed  CAS  Google Scholar 

  33. Hao L, Du M, Lopez-Campistrous A, Fernandez-Patron C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ Res. 2004;94(1):68–76.

    PubMed  Article  CAS  Google Scholar 

  34. • Wang X, Oka T, Chow FL, et al.: Tumor necrosis factor-alpha-converting enzyme is a key regulator of agonist-induced cardiac hypertrophy and fibrosis. Hypertension 2009;54(3):575–582. This article demonstrates that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TNF-α–converting enzyme by transcriptional regulation of ADAM-12 and MMP-2.

    PubMed  Article  CAS  Google Scholar 

  35. •• Odenbach J, Wang X, Cooper S, et al.: MMP-2 mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and TACE. Hypertension 2010;57(1):123–130. This article demonstrates that in the angiotensin II–induced hypertension model, MMP-7 and TNF-α–converting enzyme mediate fibrosis and hypertrophy and induce MMP-2 upregulation. The MMP-2 induces hypertension without hypertrophy.

    PubMed  Article  Google Scholar 

  36. • Butler GS, Dean RA, Morrison CJ, Overall CM: Identification of cellular MMP substrates using quantitative proteomics: isotope-coded affinity tags (ICAT) and isobaric tags for relative and absolute quantification (iTRAQ). Methods Mol Biol 2010;622:451–470. This paper describes a quantitative proteomics and mass spectrometry technique to identify protease substrates in a cell.

    PubMed  Article  CAS  Google Scholar 

  37. Overall CM, McQuibban GA, Clark-Lewis I. Discovery of chemokine substrates for matrix metalloproteinases by exosite scanning: a new tool for degradomics. Biol Chem. 2002;383(7–8):1059–66.

    PubMed  Article  CAS  Google Scholar 

  38. • Prudova A, Auf dem Keller U, Butler GS, Overall CM: Multiplex N-terminome analysis of MMP-2 and MMP-9 substrate degradomes by iTRAQ-TAILS quantitative proteomics. Mol Cell Proteomics 2010;9(5):894–911. This paper reports the development of a method for proteome-wide detection of protease-generated neo-N-termini.

    PubMed  Article  CAS  Google Scholar 

  39. Martinez A, Oh HR, Unsworth EJ, et al. Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator. Biochem J. 2004;383(Pt. 3):413–8.

    PubMed  CAS  Google Scholar 

  40. Lekgabe ED, Kiriazis H, Zhao C, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005;46(2):412–8.

    PubMed  Article  CAS  Google Scholar 

  41. Tostes RC, Touyz RM, He G, et al. Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2002;39(6):892–900.

    PubMed  Article  CAS  Google Scholar 

  42. Xue H, Zhang YL, Liu GS, Wang H. A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2005;315(2):501–9.

    PubMed  Article  CAS  Google Scholar 

  43. Camp TM, Smiley LM, Hayden MR, Tyagi SC. Mechanism of matrix accumulation and glomerulosclerosis in spontaneously hypertensive rats. J Hypertens. 2003;21(9):1719–27.

    PubMed  Article  CAS  Google Scholar 

  44. • Tran ED, DeLano FA, Schmid-Schönbein GW: Enhanced matrix metalloproteinase activity in the spontaneously hypertensive rat: VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction. J Vasc Res 2010;47(5):423–431. This paper demonstrates that extracellular-domain VEGFR-2 receptor cleavage by MMPs is a basis for endothelial apoptosis and capillary rarefaction in the SHR.

    PubMed  Article  CAS  Google Scholar 

  45. DeLano FA, Schmid-Schönbein GW. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension. 2008;52(2):415–23.

    PubMed  Article  CAS  Google Scholar 

  46. Tran E, Yang M, Chen A, et al. Matrix metalloproteinase activity causes VEGFR-2 cleavage and microvascular rarefaction in rat mesentery. Microcirculation. 2011;18:1–10.

    Article  Google Scholar 

  47. • Rodrigues SF, Tran ED, Fortes ZB, Schmid-Schönbein GW: Matrix metalloproteinases cleave the beta2-adrenergic receptor in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2010;299(1):H25-35. This article demonstrates that extracellular domain vasodilatory receptor cleavage by MMPs is a basis for arteriolar constriction and elevated blood pressure in the SHR.

    PubMed  Article  CAS  Google Scholar 

  48. Schmid-Schönbein GW, Zweifach BW, DeLano FA, Chen P. Microvascular tone in a skeletal muscle of spontaneously hypertensive rats. Hypertension. 1987;9:164–71.

    PubMed  Google Scholar 

  49. Potenza MA, Marasciulo FL, Chieppa DM, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol. 2005;289(2):H813–822.

    PubMed  Article  CAS  Google Scholar 

  50. Delano FA, Zhang H, Tran EE, et al. A new hypothesis for insulin resistance in hypertension due to receptor cleavage. Expert Rev Endocrinol Metab. 2010;5(1):149–58.

    PubMed  CAS  Google Scholar 

  51. Bohlen HG. The microcirculation in hypertension. J Hypertens Suppl. 1989;7(4):S117–124.

    PubMed  CAS  Google Scholar 

  52. Penna GL, Garbero Rde F, Neves MF, et al. Treatment of essential hypertension does not normalize capillary rarefaction. Clinics (Sao Paulo). 2008;63(5):613–8.

    Article  Google Scholar 

  53. Noon JP, Walker BR, Webb DJ, et al. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest. 1997;99(8):1873–9.

    PubMed  Article  CAS  Google Scholar 

  54. Tran ED, Schmid-Schönbein GW. An in-vivo analysis of capillary stasis and endothelial apoptosis in a model of hypertension. Microcirculation. 2007;14(8):793–804.

    PubMed  Article  CAS  Google Scholar 

  55. Lim HH, DeLano FA, Schmid-Schönbein GW. Life and death cell labeling in the microcirculation of the spontaneously hypertensive rat. J Vasc Res. 2001;38(3):228–36.

    PubMed  Article  CAS  Google Scholar 

  56. Murfee WL, Schmid-Schönbein GW. Chapter 12. Structure of microvascular networks in genetic hypertension. Methods Enzymol. 2008;444:271–84.

    PubMed  Article  CAS  Google Scholar 

  57. Wang H, Olszewski B, Rosebury W, et al. Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression. Biochem Biophys Res Commun. 2004;315(2):363–8.

    PubMed  Article  CAS  Google Scholar 

  58. • Chen AY, DeLano FA, Valdez SR, et al.: Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat. Am J Physiol Cell Physiol 2010;299(6):C1441-1449. This is a demonstration of extracellular domain chemotactic receptor cleavage in the SHR by MMPs as a contribution to attenuated chemotactic and fluid shear stress response in leukocytes.

    PubMed  Article  CAS  Google Scholar 

  59. Makino A, Prossnitz ER, Bünemann M, et al. G Protein-coupled receptors serve as mechanosensors for fluid shear stress in neutrophils. Am J Physiol Cell Physiol. 2006;290:C1633–9.

    PubMed  Article  CAS  Google Scholar 

  60. Fukuda S, Yasu T, Kobayashi N, et al. Contribution of fluid shear response in leukocytes to hemodynamic resistance in the spontaneously hypertensive rat. Circ Res. 2004;95(1):100–8.

    PubMed  Article  CAS  Google Scholar 

  61. Schmid-Schönbein GW, Seiffge D, DeLano FA, et al. Leukocyte counts and activation in spontaneously hypertensive and normotensive rats. Hypertension. 1991;17:323–30.

    PubMed  Google Scholar 

  62. Tong S, Neboori HJ, Tran ED, Schmid-Schönbein GW. Constitutive expression and enzymatic cleavage of ICAM-1 in the spontaneously hypertensive rat. J Vasc Res. 2011;48:386–96.

    PubMed  Article  CAS  Google Scholar 

  63. Pot C, Chen AY, Ha JN, Schmid-Schönbein GW: Proteolytic cleavage of the red blood cell glycocalyx in a genetic form of hypertension. Cell Mol Bioeng 2011. doi:10.1007/s12195-011-0180-0.

  64. Yang Y, Estrada EY, Thompson JF, et al. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697–709.

    PubMed  CAS  Google Scholar 

  65. Valdez SR. Serotonin 5HT-1A Receptor Density in the Brain of Spontaneously Hypertensive Rats. M.S. Thesis. La Jolla, Univ. Calif. San Diego; 2010.

  66. Kuo TB, Shaw FZ, Lai CJ, et al. Changes in sleep patterns in spontaneously hypertensive rats. Sleep. 2004;27(3):406–12.

    PubMed  Google Scholar 

  67. Peterson JT. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Fail Rev. 2004;9(1):63–79.

    PubMed  Article  CAS  Google Scholar 

  68. Castro MM, Tanus-Santos JE, Gerlach RF: Matrix metalloproteinases: targets for doxycycline to prevent the vascular alterations of hypertension. Pharmacol Res 2011 Apr 9 (Epub ahead of print).

  69. Clark IM, Swingler TE, Sampieri CL, Edwards DR. The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008;40(6–7):1362–78.

    PubMed  Article  CAS  Google Scholar 

  70. • Wu KI, Schmid-Schönbein GW: Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat. Hypertension 2011;57(2):261–268. This is a demonstration of NFκB-dependent MMP overexpression, vasodilatory receptor cleavage, and elevated blood pressure in the SHR.

    PubMed  Article  CAS  Google Scholar 

  71. Liebetrau M, Burggraf D, Wunderlich N, et al. ACE inhibition reduces activity of the plasminogen/plasmin and MMP systems in the brain of spontaneous hypertensive stroke-prone rats. Neurosci Lett. 2005;376(3):205–9.

    PubMed  Article  CAS  Google Scholar 

  72. Yamamoto D, Takai S. Pharmacological implications of MMP-9 inhibition by ACE inhibitors. Curr Med Chem. 2009;16(11):1349–54.

    PubMed  Article  CAS  Google Scholar 

  73. Pahor M, Psaty BM, Alderman MH, et al. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care. 2000;23(7):888–92.

    PubMed  Article  CAS  Google Scholar 

  74. Gillespie EL, White CM, Kardas M, et al. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Diabetes Care. 2005;28(9):2261–6.

    PubMed  Article  CAS  Google Scholar 

  75. Ryan ME, Ramamurthy NS, Sorsa T, Golub LM. MMP-mediated events in diabetes. Ann N Y Acad Sci. 1999;878:311–34.

    PubMed  Article  CAS  Google Scholar 

  76. Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metalloproteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med. 2006;208(2):117–22.

    PubMed  Article  CAS  Google Scholar 

  77. Fernandez-Patron C, Zhang Y, Radomski MW, et al. Rapid release of matrix metalloproteinase (MMP)-2 by thrombin in the rat aorta: modulation by protein tyrosine kinase/phosphatase. Thromb Haemost. 1999;82(4):1353–7.

    PubMed  CAS  Google Scholar 

  78. Rosario HS, Waldo SW, Becker SA, Schmid-Schönbein GW. Pancreatic trypsin increases matrix metalloproteinase-9 accumulation and activation during acute intestinal ischemia-reperfusion in the rat. Am J Pathol. 2004;164(5):1707–16.

    PubMed  Article  CAS  Google Scholar 

  79. Asanuma K, Magid R, Johnson C, et al. Uniaxial strain upregulates matrix-degrading enzymes produced by human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2003;284(5):H1778–1784.

    PubMed  CAS  Google Scholar 

  80. Grote K, Flach I, Luchtefeld M, et al. Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res. 2003;92(11):e80–86.

    PubMed  Article  CAS  Google Scholar 

  81. Cummins PM, von Offenberg Sweeney N, Killeen MT, et al. Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. Am J Physiol Heart Circ Physiol. 2007;292(1):H28–42.

    PubMed  Article  CAS  Google Scholar 

  82. Deryugina EI, Ratnikov B, Monosov E, et al. MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res. 2001;263(2):209–23.

    PubMed  Article  CAS  Google Scholar 

  83. Guo D, Kassiri Z, Basu R, et al. Loss of PI3Kgamma enhances cAMP-dependent MMP remodeling of the myocardial N-cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress. Circ Res. 2010;107(10):1275–89.

    PubMed  Article  CAS  Google Scholar 

  84. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006;11:1696–701.

    PubMed  Article  CAS  Google Scholar 

  85. Weiss SJ, Peppin G, Ortiz X, et al. Oxidative autoactivation of latent collagenase by human neutrophils. Science. 1985;227(4688):747–9.

    PubMed  Article  CAS  Google Scholar 

  86. Fontana V, Silva PS, Belo VA, et al. Consistent alterations of circulating matrix metalloproteinases levels in untreated hypertensives and in spontaneously hypertensive rats: a relevant pharmacological target. Basic Clin Pharmacol Toxicol. 2011;109(2):130–7.

    PubMed  Article  CAS  Google Scholar 

  87. Lefkowitz RB, Schmid-Schönbein GW, Heller MJ. Whole blood assay for elastase, chymotrypsin, matrix metalloproteinase-2, and matrix metalloproteinase-9 activity. Anal Chem. 2010;82(19):8251–8.

    PubMed  Article  CAS  Google Scholar 

  88. Friese RS, Rao F, Khandrika S, et al. Matrix metalloproteinases: discrete elevations in essential hypertension and hypertensive end-stage renal disease. Clin Exp Hypertens. 2009;31(7):521–33.

    PubMed  Article  CAS  Google Scholar 

  89. Papadopoulos DP, Makris TK, Krespi PG, et al. Changes in metalloproteinases in healthy normotensive patients with high-normal blood pressure. Eur Cytokine Netw. 2005;16(3):211–4.

    PubMed  CAS  Google Scholar 

  90. Derosa G, D’Angelo A, Ciccarelli L, et al. Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension. Endothelium. 2006;13(3):227–31.

    PubMed  Article  CAS  Google Scholar 

  91. Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res. 2007;30(10):959–63.

    PubMed  Article  CAS  Google Scholar 

  92. Ishikawa J, Kario K, Matsui Y, et al. Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy. Hypertens Res. 2005;28(12):995–1001.

    PubMed  Article  CAS  Google Scholar 

  93. Yasmin, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(2):372.

    PubMed  Article  CAS  Google Scholar 

  94. Hirono O, Fatema K, Nitobe J, et al. Long-term effects of benidipine hydrochloride on severe left ventricular hypertrophy and collagen metabolism in patients with essential hypertension. J Cardiol. 2002;39(4):195–204.

    PubMed  Google Scholar 

  95. Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006;113(17):2089–96.

    PubMed  Article  CAS  Google Scholar 

  96. Zervoudaki A, Economou E, Pitsavos C, et al. The effect of Ca2+ channel antagonists on plasma concentrations of matrix metalloproteinase-2 and −9 in essential hypertension. Am J Hypertens. 2004;17(3):273–6.

    PubMed  Article  CAS  Google Scholar 

  97. Li-Saw-Hee FL, Edmunds E, Blann AD, et al. Matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 levels in essential hypertension. Relationship to left ventricular mass and anti-hypertensive therapy. Int J Cardiol. 2000;75(1):43–7.

    PubMed  Article  CAS  Google Scholar 

  98. Laviades C, Varo N, Fernandez J, et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation. 1998;98(6):535–40.

    PubMed  CAS  Google Scholar 

  99. Lacchini R, Jacob-Ferreira AL, Luizon MR, et al. Matrix metalloproteinase 9 gene haplotypes affect left ventricular hypertrophy in hypertensive patients. Clin Chim Acta. 2010;411(23–24):1940–4.

    PubMed  Article  CAS  Google Scholar 

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Funding

NIH Grant HL 10881 and an unrestricted research gift from Leading Ventures.

Disclosure

Dr. Schmid-Schönbein is scientific advisor to Leading Ventures and owns interest in InhibeX, a company by Leading Ventures.

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  1. Department of Bioengineering, Institute of Engineering in Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0412, USA

    Geert W. Schmid-Schönbein

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Schmid-Schönbein, G.W. An Emerging Role of Degrading Proteinases in Hypertension and the Metabolic Syndrome: Autodigestion and Receptor Cleavage. Curr Hypertens Rep 14, 88–96 (2012). https://doi.org/10.1007/s11906-011-0240-9

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Keywords

  • Matrix metalloproteinase
  • MMP
  • ADAM
  • Metabolic syndrome
  • Hypertrophy
  • Insulin resistance
  • Capillary rarefaction
  • Immune suppression
  • Insulin receptor
  • Beta-adrenergic receptor
  • Vascular endothelial growth factor receptor
  • NF-kappaB
  • Spontaneously hypertensive rat
  • Essential hypertension
  • Microcirculation
  • Artery
  • Arteriole
  • Extracellular matrix protein
  • Proteinase inhibitor
  • Angiotensin-converting enzyme
  • Angiotensin
  • Hypertension
  • Metabolic syndrome
  • Pathogenesis