Skip to main content
SpringerLink
Log in

Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague–Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible-nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-α, transforming growth factor (TGF)-β1 and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H, McGrady G, Song XY, Wahl SM (2000) Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med 6:1147–1153

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Jugdutt BI, Jelani A, Palaniyappan A, Idikio H, Uweira RE, Menon V, Jugdutt CE (2010) Aging-related changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model. Effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation 122:341–351

    Article  PubMed  CAS  Google Scholar 

  4. Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53:31–47

    Article  PubMed  CAS  Google Scholar 

  5. Jugdutt BI (2003) Ventricular remodeling post-infarction and the extracellular collagen matrix. When is enough enough? Circulation 108:1395–1403

    Article  PubMed  Google Scholar 

  6. Jugdutt BI (2003) Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets, Cardiovas Haemat Dis 3:1–30

    Article  CAS  Google Scholar 

  7. Jugdutt BI, Joljart MJ, Khan MI (1996) Rate of collagen deposition during healing after myocardial infarction in the rat and dog models: mechanistic insights into ventricular remodeling. Circulation 94:94–101

    Article  PubMed  CAS  Google Scholar 

  8. Jugdutt BI (1987) Left ventricular rupture threshold during the healing phase after myocardial infarction in the dog. Can J Physiol Pharmacol 65:307–316

    Article  PubMed  CAS  Google Scholar 

  9. Jugdutt BI (1988) Effect of nitroglycerin and ibuprofen on left ventricular topography and rupture threshold during healing after myocardial infarction in the dog. Can J Physiol Pharmacol 66:385–395

    Article  PubMed  CAS  Google Scholar 

  10. Pfeffer MA, Braunwald E (1990) Ventricular remodelling after myocardial infarction. Circulation 81:1161–1172

    Article  PubMed  CAS  Google Scholar 

  11. Jugdutt BI (1990) Identification of patients prone to infarct expansion by the degree of regional shape distortion on an early two-dimensional echocardiogram after myocardial infarction. Clin Cardiol 13:28–40

    Article  PubMed  CAS  Google Scholar 

  12. Gaudron P, Eilles C, Kugler I, Ertl G (1993) Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation 87:755–763

    Article  PubMed  CAS  Google Scholar 

  13. Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D (2002) Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106:2351–2357

    Article  PubMed  Google Scholar 

  14. Reffelmann T, Hale SL, Dow JS, Kloner RA (2003) No-reflow phenomenon persists long-term after ischemia/reperfusion in the rat and predicts infarct expansion. Circulation 108:2911–2917

    Article  PubMed  Google Scholar 

  15. Pfeffer JM, Pfeffer MA, Braunwald E (1985) Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 57:84–95

    Article  PubMed  CAS  Google Scholar 

  16. Palaniyappan A, Uwiera RER, Idikio H, Jugdutt BI (2009) Comparison of vasopeptidase inhibitor omapatrilat and angiotensin II type 1 receptor blocker candesartan on extracellular matrix, myeloperoxidase, cytokines and ventricular remodeling during healing after reperfused myocardial infarction. Mol Cell Biochem 321:9–22

    Article  PubMed  CAS  Google Scholar 

  17. Pfeffer MA, Greaves SC, Arnold JM, Glynn RJ, LaMotte FS, Lee RT, Menapace FJ Jr, Rapaport E, Ridker PM, Rouleau JL, Solomon SD, Hennekens CH, For The Healing and Early Afterload Reducing Therapy (HEART) trial investigators (1997) Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial. Circulation 95:2643–2651

    Article  PubMed  CAS  Google Scholar 

  18. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, For The CHARM Investigators and Committees (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall trial. Lancet 362:759–766

    Article  PubMed  CAS  Google Scholar 

  19. 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  PubMed  CAS  Google Scholar 

  20. Schellings MW, Vanhoutte D, Swinnen M, Cleutjens JP, Debets J, van Leeuwen RE, d’Hooge J, Van de Werf F, Carmeliet P, Pinto YM, Sage EH, Heymans S (2009) Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction. J Exp Med 206:113–123

    Article  PubMed  CAS  Google Scholar 

  21. Fedak PW, Moravec CS, McCarthy PM, Altamentova SM, Wong AP, Skrtic M, Verma S, Weisel RD, Li RK (2006) Altered expression of disintegrin metalloproteinases and their inhibitor in human dilated cardiomyopathy. Circulation 113:238–245

    Article  PubMed  CAS  Google Scholar 

  22. Jugdutt BI, Menon V (2004) AT2 receptor and apoptosis during AT1 receptor blockade in reperfused myocardial infarction in the rat. Mol Cell Biochem 262:203–214

    Article  PubMed  CAS  Google Scholar 

  23. Jugdutt BI, Menon V (2004) Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in dog and rat models of in vivo reperfused myocardial infarction. J Card Fail 10:74–82

    Article  PubMed  CAS  Google Scholar 

  24. Jugdutt BI (2008) Aging and remodeling during healing of the wounded heart: current therapies and novel drug targets. Curr Drug Targets 9:325–344

    Article  PubMed  CAS  Google Scholar 

  25. Ørn S, Manhenke C, Greve OJ, Larsen AI, Bonarjee VV, Edvardsen T, Dickstein K (2009) Microvascular obstruction is a major determinant of infarct healing and subsequent left ventricular remodelling following primary percutaneous coronary intervention. Eur Heart J 30:1978–1985

    Article  PubMed  Google Scholar 

  26. Nahrendorf M, Pittet MJ, Swirski FK (2010) Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121:2437–2445

    Article  PubMed  Google Scholar 

  27. Frangogiannis NG (2012) Regulation of the inflammatory response in cardiac repair. Circ Res 110:159–173

    Article  PubMed  CAS  Google Scholar 

  28. Angelov N, Moutsopoulos N, Jeong M-J, Nares S, Ashcroft G (2004) Aberrant mucosal wound repair in the absence of secretory leukocyte protease inhibitor. Thromb Haemost 92:288–297

    PubMed  CAS  Google Scholar 

  29. Lapointe N, Blais C Jr, Adam A, Parker T, Sirois MG, Gosselin H, Clément R, Rouleau JL (2002) Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat. J Am Coll Cardiol 39:1692–1698

    Article  PubMed  CAS  Google Scholar 

  30. Jugdutt BI (2008) Pleiotropic effects of cardiac drugs on healing post MI. The good, bad and ugly. Heart Failure Rev 13:439–452

    Article  Google Scholar 

  31. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E (2004) Omapatrilat and enalapiril in patients with hypertension: the omapatrilat cardiovascular treatment vs enalapril (OCTAVE) trial. Am J Hypertens 17:103–111

    Article  PubMed  CAS  Google Scholar 

  32. Solomon SD, Skali H, Bourgoun M, Fang J, Ghali JK, Martelet M, Wojciechowski D, Ansmite B, Skards J, Laks T, Henry D, Packer M, Pfeffer MA, For The OVERTURE investigators (2005) Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular siez and function in patients with heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE) ehocardiographic study. Am Herat J 150:257–262

    Article  CAS  Google Scholar 

  33. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJV for the PARAMOUNT investigators (2012) The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized clinical trial. Lancet. http://dx.doi.org/10.1016/S0140-6736(12)61227-6. Accessed Aug 2012

  34. ClinicalTrials.gov (2012) Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in patients with heart failure (PARADIGM-HF). http://ClinicalTrials.gov/ct2//show/NCT01035255. Accessed Aug 2012

Download references

Acknowledgments

This study was supported in part by a grant from the Heart and Stroke Foundation of Canada, Ottawa, Ontario.

Conflict of Interest

None.

Author information

Authors and Affiliations

  1. Division of Cardiology and Department of Medicine, 2C2 Walter MacKenzie Health Sciences Centre, University of Alberta, Edmonton, AB, T6G 2R7, Canada

    Vijay Menon, Catherine Jugdutt & Bodh I. Jugdutt

  2. Cardiovascular Research Group, University of Alberta, Edmonton, Canada

    Ariv Palaniyappan & Bodh I. Jugdutt

  3. Health Sciences Laboratory Animal Services, University of Alberta, Edmonton, Canada

    Richard R. E. Uwiera

  4. Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Canada

    Halliday Idikio

Authors
  1. Ariv Palaniyappan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard R. E. Uwiera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Halliday Idikio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vijay Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Catherine Jugdutt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bodh I. Jugdutt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bodh I. Jugdutt.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palaniyappan, A., Uwiera, R.R.E., Idikio, H. et al. Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction. Mol Cell Biochem 376, 175–188 (2013). https://doi.org/10.1007/s11010-013-1565-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1565-2

Keywords

Search

Navigation