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Role of osteopontin in heart failure associated with aging

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Abstract

Cardiovascular disease is one of the leading causes of death in the elderly. Much of the morbidity and mortality in the elderly is attributable to acute ischemic events leading to myocardial infarction (MI) and death of cardiac myocytes. Evidence has been provided that aging associated with adverse remodeling post MI as demonstrated by less effective myocardial repair, greater infarct expansion, and septal hypertrophy. Expression of osteopontin (OPN) increases in the heart post MI. Transgenic mice studies suggest that increased expression of OPN plays a protective role in post-MI LV remodeling by modulating collagen deposition and fibrosis. OPN, a multifunctional protein, has the potential to influence the molecular and cellular changes associated with infarct healing. The post-MI infarct healing process involves temporarily overlapping phases that include the following—(1) inflammation with migration and adhesion of neutrophils and macrophages, phagocytosis and inflammatory gene expression; (2) tissue repair with fibroblast adhesion and proliferation, myofibroblast differentiation, extracellular matrix deposition and scar formation; and (3) structural and functional remodeling of infarcted and non-infarcted myocardium through cardiac myocyte apoptosis, hypertrophy and myocardial angiogenesis. This review is focused on the expression of OPN in the heart post MI and its role in various phases of infarct healing.

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References

  1. Maggioni AP, Maseri A, Fresco C, Franzosi MG, Mauri F, Santoro E, Tognoni G (1993) Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. The Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2). N Engl J Med 329:1442–1448

    Article  CAS  PubMed  Google Scholar 

  2. St John SM, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E (1997) Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 96:3294–3299

    Google Scholar 

  3. Jugdutt BI, Jelani A (2008) Aging and defective healing, adverse remodeling, and blunted post-conditioning in the reperfused wounded heart. J Am Coll Cardiol 51:1399–1403

    Article  PubMed  Google Scholar 

  4. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA (2006) Controversies in ventricular remodelling. Lancet 367:356–367

    Article  PubMed  Google Scholar 

  5. Frangogiannis NG (2006) The mechanistic basis of infarct healing. Antioxid Redox Signal 8:1907–1939

    Article  CAS  PubMed  Google Scholar 

  6. Gould KE, Taffet GE, Michael LH, Christie RM, Konkol DL, Pocius JS, Zachariah JP, Chaupin DF, Daniel SL, Sandusky GE Jr, Hartley CJ, Entman ML (2002) Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure. Am J Physiol Heart Circ Physiol 282:H615–H621

    CAS  PubMed  Google Scholar 

  7. Janicki JS, Brower GL (2002) The role of myocardial fibrillar collagen in ventricular remodeling and function. J Card Fail 8:S319–S325

    Article  CAS  PubMed  Google Scholar 

  8. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87:1285–1342

    Article  CAS  PubMed  Google Scholar 

  9. Wang KX, Denhardt DT (2008) Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev 19:333–345

    Article  CAS  PubMed  Google Scholar 

  10. Scatena M, Liaw L, Giachelli CM (2007) Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 27:2302–2309

    Article  CAS  PubMed  Google Scholar 

  11. Singh M, Ananthula S, Milhorn DM, Krishnaswamy G, Singh K (2007) Osteopontin: a novel inflammatory mediator of cardiovascular disease. Front Biosci 12:214–221

    Article  CAS  PubMed  Google Scholar 

  12. Singh M, Foster CR, Dalal S, Singh K (2009) Osteopontin: role in extracellular matrix deposition and myocardial remodeling post-MI. J Mol Cell Cardiol (Epub ahead of print)

  13. Kazanecki CC, Uzwiak DJ, Denhardt DT (2007) Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J Cell Biochem 102:912–924

    Article  CAS  PubMed  Google Scholar 

  14. Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA (1995) Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. J Biol Chem 270:28471–28478

    Article  CAS  PubMed  Google Scholar 

  15. Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L, Jenkins AW, Wang J, Sawyer DB, Bing OH, Apstein CS, Colucci WS, Singh K (2001) Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin. Circ Res 88:1080–1087

    Article  CAS  PubMed  Google Scholar 

  16. Williams EB, Halpert I, Wickline S, Davison G, Parks WC, Rottman JN (1995) Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters. Circulation 92:705–709

    CAS  PubMed  Google Scholar 

  17. Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA (1997) Myocardial osteopontin expression is associated with left ventricular hypertrophy. Circulation 96:3063–3071

    CAS  PubMed  Google Scholar 

  18. Singh K, Sirokman G, Communal C, Robinson KG, Conrad CH, Brooks WW, Bing OH, Colucci WS (1999) Myocardial osteopontin expression coincides with the development of heart failure. Hypertension 33:663–670

    CAS  PubMed  Google Scholar 

  19. Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K (2004) Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens 17:188–193

    Article  CAS  PubMed  Google Scholar 

  20. Subramanian V, Krishnamurthy P, Singh K, Singh M (2007) Lack of osteopontin improves cardiac function in streptozotocin-induced diabetic mice. Am J Physiol Heart Circ Physiol 292:H673–H683

    Article  CAS  PubMed  Google Scholar 

  21. Szalay G, Sauter M, Haberland M, Zuegel U, Steinmeyer A, Kandolf R, Klingel K (2009) Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host. Circ Res 104:851–859

    Article  CAS  PubMed  Google Scholar 

  22. Tamura A, Shingai M, Aso N, Hazuku T, Nasu M (2003) Osteopontin is released from the heart into the coronary circulation in patients with a previous anterior wall myocardial infarction. Circ J 67:742–744

    Article  CAS  PubMed  Google Scholar 

  23. Suezawa C, Kusachi S, Murakami T, Toeda K, Hirohata S, Nakamura K, Yamamoto K, Koten K, Miyoshi T, Shiratori Y (2005) Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. J Lab Clin Med 145:33–40

    Article  CAS  PubMed  Google Scholar 

  24. Komatsubara I, Murakami T, Kusachi S, Nakamura K, Hirohata S, Hayashi J, Takemoto S, Suezawa C, Ninomiya Y, Shiratori Y (2003) Spatially and temporally different expression of osteonectin and osteopontin in the infarct zone of experimentally induced myocardial infarction in rats. Cardiovasc Pathol 12:186–194

    Article  CAS  PubMed  Google Scholar 

  25. Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, Michael LH, Rollins BJ, Entman ML, Frangogiannis NG (2005) CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 96:881–889

    Article  CAS  PubMed  Google Scholar 

  26. Xie Z, Singh M, Singh K (2004) Osteopontin modulates myocardial hypertrophy in response to chronic pressure overload in mice. Hypertension 44:826–831

    Article  CAS  PubMed  Google Scholar 

  27. Bujak M, Kweon HJ, Chatila K, Li N, Taffet G, Frangogiannis NG (2008) Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol 51:1384–1392

    Article  PubMed  Google Scholar 

  28. Jugdutt BI, Palaniyappan A, Uwiera RR, Idikio H (2009) Role of healing-specific-matricellular proteins and matrix metalloproteinases in age-related enhanced early remodeling after reperfused STEMI in dogs. Mol Cell Biochem 322:25–36

    Article  CAS  PubMed  Google Scholar 

  29. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA (1996) Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 98:2218–2227

    Article  CAS  PubMed  Google Scholar 

  30. Xie Z, Singh M, Singh K (2004) ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. J Cell Physiol 198:399–407

    Article  CAS  PubMed  Google Scholar 

  31. Xie Z, Pimental DR, Lohan S, Vasertriger A, Pligavko C, Colucci WS, Singh K (2001) Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J Cell Physiol 188:132–138

    Article  CAS  PubMed  Google Scholar 

  32. Kusuyama T, Yoshiyama M, Omura T, Nishiya D, Enomoto S, Matsumoto R, Izumi Y, Akioka K, Takeuchi K, Iwao H, Yoshikawa J (2005) Angiotensin blockade inhibits osteopontin expression in non-infarcted myocardium after myocardial infarction. J Pharmacol Sci 98:283–289

    Article  CAS  PubMed  Google Scholar 

  33. Zhang YL, Zhou SX, Lei J, Yuan GY, Wang JF (2008) Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction. Chin Med J (Engl) 121:2192–2196

    CAS  Google Scholar 

  34. Krishnamurthy P, Peterson JT, Subramanian V, Singh M, Singh K (2009) Inhibition of matrix metalloproteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction. Mol Cell Biochem 322:53–62

    Article  CAS  PubMed  Google Scholar 

  35. Koh A, da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R (2007) Role of osteopontin in neutrophil function. Immunology 122:466–475

    Article  CAS  PubMed  Google Scholar 

  36. McKee MD, Nanci A (1996) Secretion of osteopontin by macrophages and its accumulation at tissue surfaces during wound healing in mineralized tissues: a potential requirement for macrophage adhesion and phagocytosis. Anat Rec 245:394–409

    Article  CAS  PubMed  Google Scholar 

  37. Nystrom T, Duner P, Hultgardh-Nilsson A (2007) A constitutive endogenous osteopontin production is important for macrophage function and differentiation. Exp Cell Res 313:1149–1160

    Article  PubMed  Google Scholar 

  38. Frangogiannis NG, Mendoza LH, Lindsey ML, Ballantyne CM, Michael LH, Smith CW, Entman ML (2000) IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury. J Immunol 165:2798–2808

    CAS  PubMed  Google Scholar 

  39. Lenga Y, Koh A, Perera AS, McCulloch CA, Sodek J, Zohar R (2008) Osteopontin expression is required for myofibroblast differentiation. Circ Res 102:319–327

    Article  CAS  PubMed  Google Scholar 

  40. Zahradka P (2008) Novel role for osteopontin in cardiac fibrosis. Circ Res 102:270–272

    Article  CAS  PubMed  Google Scholar 

  41. Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu L, Morimoto J, Rittling SR, Denhardt D, Kitabatake A, Uede T (2004) Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension 43:1195–1201

    Article  CAS  PubMed  Google Scholar 

  42. Lindsey ML, Mann DL, Entman ML, Spinale FG (2003) Extracellular matrix remodeling following myocardial injury. Ann Med 35:316–326

    Article  CAS  PubMed  Google Scholar 

  43. Xie Z, Singh M, Siwik DA, Joyner WL, Singh K (2003) Osteopontin inhibits interleukin-1beta-stimulated increases in matrix metalloproteinase activity in adult rat cardiac fibroblasts: role of protein kinase C-zeta. J Biol Chem 278:48546–48552

    Article  CAS  PubMed  Google Scholar 

  44. Kaludercic N, Lindsey ML, Tavazzi B, Lazzarino G, Paolocci N (2008) Inhibiting metalloproteases with PD 166793 in heart failure: impact on cardiac remodeling and beyond. Cardiovasc Ther 26:24–37

    CAS  PubMed  Google Scholar 

  45. Persy VP, Verhulst A, Ysebaert DK, De Greef KE, De Broe ME (2003) Reduced postischemic macrophage infiltration and interstitial fibrosis in osteopontin knockout mice. Kidney Int 63:543–553

    Article  CAS  PubMed  Google Scholar 

  46. Yumoto K, Ishijima M, Rittling SR, Tsuji K, Tsuchiya Y, Kon S, Nifuji A, Uede T, Denhardt DT, Noda M (2002) Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc Natl Acad Sci U S A 99:4556–4561

    Article  CAS  PubMed  Google Scholar 

  47. Wang KX, Shi Y, Denhardt DT (2007) Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production. Proc Natl Acad Sci U S A 104:14777–14782

    Article  CAS  PubMed  Google Scholar 

  48. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H (2006) Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47:711–717

    Article  CAS  PubMed  Google Scholar 

  49. Ren G, Michael LH, Entman ML, Frangogiannis NG (2005) Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem 50:71–79

    Google Scholar 

  50. Zhao X, Johnson JN, Singh K, Singh M (2007) Impairment of myocardial angiogenic response in the absence of osteopontin. Microcirculation 14:233–240

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by National Institutes of Health (Grant numbers HL-091405 and HL-092459) and a Merit Review Grant from the Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Physiology, James H Quillen College of Medicine, East Tennessee State University, PO Box 70576, Johnson City, TN, 37614, USA

    Mahipal Singh, Cerrone R. Foster, Suman Dalal & Krishna Singh

  2. James H Quillen Veterans Affairs Medical Center, Johnson City, TN, USA

    Krishna Singh

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  1. Mahipal Singh
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  2. Cerrone R. Foster
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  3. Suman Dalal
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  4. Krishna Singh
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Correspondence to Krishna Singh.

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Singh, M., Foster, C.R., Dalal, S. et al. Role of osteopontin in heart failure associated with aging. Heart Fail Rev 15, 487–494 (2010). https://doi.org/10.1007/s10741-010-9158-6

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