Skip to main content
SpringerLink
Log in

AT1receptor blockade alters metabolic, functional and structural proteins after reperfused myocardial infarction: Detection using proteomics

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

An Erratum to this article was published on 22 December 2006

Abstract

Angiotensin II (AngII) type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and necrosis after reperfused myocardial infarction (RMI) and proteomics can detect changes in protein levels after injury. We applied proteomics to detect changes in levels of specific protein in the ischemic zone (IZ) and non-ischemic zone (NIZ) of dog hearts after in vivo RMI (90 min of anterior ischemia; 120 min of reperfusion) and treatment with intravenous vehicle (control) and the ARBs valsartan or irbesartan (10 mg/kg) over 30 min before RMI. We also assessed LV function, infarction and apoptosis. Both ARBs limited the RMI-induced LV dysfunction, infarct size and apoptosis. Proteomics detected differential expression of 5 randomly selected proteins in the IZ compared to the NIZ after RMI: decrease in α subunit of ATP synthase isoform precursor (consistent with increased conversion to α subunit under metabolic stress), M chain creatine kinase (consistent with cellular damage) and ventricular myosin light chain-1 (consistent with structural damage and decreased contractility); and increase in NAD+-isocitrate dehydrogenase (ICDH) and α subunit and ATP synthase D chain (mitochondrial, consistent with metabolic dysfunction). Importantly, changes in NAD+-ICDH and ATP synthase D chain were reversed by ARB therapy. Thus, proteomics can detect regional changes in metabolic, contractile, and structural proteins after RMI and several of these proteins are favorably modified by ARBs, suggesting that they may be novel therapeutic targets. (Mol Cell Biochem 263: 179–188, 2004)

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

Similar content being viewed by others

References

  1. Braunwald E, Kloner RA: The stunned myocardium: prolonged, post-ischemic ventricular dysfunction. Circulation 66: 1146–1149, 1982

    Google Scholar 

  2. Ganz P, Ganz W: Coronary blood flow and myocardial ischemia. In: E. Braunwald, D. P. Zipes, P. Libby (eds). Heart Disease 6th edn, Vol 2. Saunders, Philadelphia 2001, pp 1087–1113

    Google Scholar 

  3. Jugdutt BI: Effect of reperfusion on ventricular mass, topography and function during healing of anterior infarction. AmJ Physiol 272: H1205–H1211, 1997

    Google Scholar 

  4. Bolli R: Mechanism of myocardial stunning. Circulation 82: 723–738, 1990

    Google Scholar 

  5. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE: Impact of left ventricular unloading after late reperfusion of canine anterior myocardial infarction on remodeling and function using isosorbide-5-mononitrate. Circulation 92: 926–934, 1995

    Google Scholar 

  6. Jugdutt BI, Schwarz-Michorowski BL, Tymchak WJ, Burton JR: Prompt improvement of left ventricular function and topography with combined reperfusion and intravenous nitroglycerin in acute myocardial infarc-tion. Cardiology 88: 170–179, 1997

    Google Scholar 

  7. Armstrong PW, Collen D: Fibrinolysis for acute myocardial infarction: current status and new horizons for pharmacological reperfusion, part 2. Circulation 103: 2987–2992, 2001

    Google Scholar 

  8. Yoshiyama M, Kim S, Yamagishi H, Omura T, Tani T, Yanagi S, Toda I, Teragaki M, Akioka K, Takeuchi K, Takeda T: Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J 128: 1–6, 1994

    Google Scholar 

  9. Youhua Z, Shouchun X: Increased vulnerability of hypertrophied my-ocardium to ischemia and reperfusion injury. Relation to cardiac renin-angiotensin system. Chin Med J 108: 28–32, 1995

    Google Scholar 

  10. Jalowy A, Schulz R, D¨ orge H, Behrends M, Heusch G: Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs. J Am Coll Cardiol 32: 1787–1796, 1998

    Google Scholar 

  11. Jugdutt BI, Xu Y, Balghith M, Moudgil R, Menon V: Cardioprotection induced by AT1R blockade after reperfused myocardial infarction: As-sociation with regional increase in AT2R, IP3R and PKC proteins and cGMP. J Cardiovasc Pharmacol Therapeut 5: 301–311, 2000

    Google Scholar 

  12. Xu Y, Menon V, Jugdutt BI: Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activa-tion of protein kinase C-å in acutely reperfused myocardial infarction. Effect of UP269-6 and losartan on AT1 and AT2 receptor expression, and IP3 receptor and PKC proteins. J Renin Angiotensin Aldosterone Syst 1: 184–195, 2000

    Google Scholar 

  13. Jugdutt BI, Balghith M: Enhanced regional AT2-receptor and PKC expression during cardioprotection induced by AT1-receptor blockade after reperfused myocardial infarction. J Renin Angiotensin Aldosterone Syst 2: 134–140, 2001

    Google Scholar 

  14. Jugdutt BI: Role of AT1 receptor blockade in reperfused myocardial infarction. In: N. S. Dhalla (ed). Signal Transduction and Cardiac Hy-pertrophy. Kluwer Academic Publishers, Boston, 2002, pp 221–236

    Google Scholar 

  15. Arrell DK, Neverova I, Van Eyk JE: Cardiovascular proteomics: Evo-lution and potential. Circ Res 88: 763–773, 2001

    Google Scholar 

  16. Xu Y, Kumar D, Dyck J, Ford WR, Clanachan AS, Lopaschuk GD, Jugdutt BI: AT1 and AT2 receptor expression and blockade after acute ischemia–reperfusion in isolated working rat hearts. Am J Physiol 282: H1206–H1215, 2002

    Google Scholar 

  17. Matsumura K, Jeremy RW, Schaper J, Becker LC: Progression of my-ocardial necrosis during reperfusion of ischemic myocardium. Circula-tion 97: 795–804, 1998

    Google Scholar 

  18. Criscione L, de Gasparo M, Buhlmayer P, Whitebread S, Ramjoue HP, Wood J: Pharmacological profile of valsartan: A potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol 110: 761–771, 1993

    Google Scholar 

  19. Culman J, von Heyer C, Piepenburg B, Rascher W, Unger T: Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. Eur J Pharmacol 367: 255–265; 1999

    Google Scholar 

  20. Balghith M, Jugdutt BI: Assessment of diastolic dysfunction after acute myocardial infarction using Doppler echocardiography. Can J Cardiol 18: 69–77, 2001

    Google Scholar 

  21. Sawicki G, Dakour J, Morrish DW: Functional proteomics of neurokinin B inthe placenta indicates a novel role in regulating cytotrophoblast antioxidant defences. Proteomics 3: 2044–2051, 2003

    Google Scholar 

  22. Perkins DN, Pappin DJ, Creasy DM, Cottrell JS: Probability-based pro-tein identification by searching sequence databases using mass spec-trometry data. Electrophoresis 20: 3551–3567, 1999

    Google Scholar 

  23. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970

    Google Scholar 

  24. Moudgil R, Menon V, Xu Y, Musat-Marcu S, Kumar D, Jugdutt BI: Postischemic apoptosis and functional recovery after angiotensin II type 1 receptor blockade in isolated working rat hearts. J Hypertens 19: 1121–1129, 2001

    Google Scholar 

  25. McGregor E, Dunn MJ: Proteomics of heart disease. Hum Mol Genet 12: R135–R144, 2003

    Google Scholar 

  26. Comte B, Vincent G, Bouchard B, Benderdour M, Des Rosiers C: Reverse flux through cardiac NADP(+)-isocitrate dehydrogenase under normoxia and ischemia. Am J Physiol 283: H1505–H1514, 2002

    Google Scholar 

  27. Werrmann JG, Cohen SM: Comparison of effects of angiotensin-converting enzyme inhibition with those of angiotensin II receptor an-tagonism on functional and metabolic recovery in postischemic working rat heart as studied by [31P] nuclear magnetic resonance. J Cardiovasc Pharmacol 24: 573–586, 1994

    Google Scholar 

  28. Van Eyk JE, Powers F, Law W, Larue C, Hodges RS, Solaro RJ: Breakdown and release of myofilament proteins during ischemia and ischemia/reperfusion in rat hearts: Identification of degradation products and effects on the pCa-force relation. Circ Res 82: 261–271, 1998

    Google Scholar 

  29. McDonough JL, Arrell DK, Van Eyk JE: Troponin I degrada-tion and covalent complex formation accompanies myocardial is-chemia/ reperfusion injury. Circ Res 84: 9–20, 1999

    Google Scholar 

  30. Yang J, Moravec CS, Sussman MA, DiPaola NR, Fu D, Hawthorn L, Mitchell CA, Young JB, Francis GS, McCarthy PM, Bond M: De-creased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays. Circu-lation 102: 3046–3052, 2000.

    Google Scholar 

  31. Rouet-Benzineb P, Buhler JM, Dreyfus P, Delcourt A, Dorent R, Peren-nec J, Crozatier B, Harf A, Lafuma C: Altered balance between matrix gelatinases (MMP-2and MMP-9)and their tissue inhibitors in human di-lated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail 1: 337–352, 1999

    Google Scholar 

  32. Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR: Cardiac remodelling in end stage heart failure: Upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart 88: 525–530, 2002

    Google Scholar 

  33. Tyagi SC, Hayden MR, Hall JE: Role of angiotensin in angiogenesis and cardiac fibrosis in heart failure. In: N.S. Dhalla, P. Zahradka, I. Dixon, R. Beamish (eds). Angiotensin II receptor blockade: Physiological and Clinical Implications. Kluwer Academic Publishers, Boston, 1998, pp 537–549

    Google Scholar 

  34. Sawicki G, Menon V, Jugdutt BI: AT1 receptor blockade upregulates TIMP-3 and improves MMP-9/TIMP-3 balance during in vivo postis-chemic myocardial reperfusion. (Abstr) Circulation 108: IV–38, 2003

    Google Scholar 

  35. Charney RH, Takahashi S, Zhao M, Sonnenblick EH, Eng C: Collagen loss in the stunned myocardium. Circulation 85: 1483–1490, 1992

    Google Scholar 

  36. Spinale FG, Mukherjee R, Iannini JP, Whitebread S, Hebbar L, Clair MJ, Melton DM, Cox MH, Thomas PB, de Gasparo M: Modulation of the renin–angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes. Circulation 96: 2397–2406, 1997

    Google Scholar 

  37. Bolli R, Marban E: Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79: 609–634, 1999

    Google Scholar 

  38. Jugdutt BI: Ventricular remodeling postinfarction and the extracellular collagen matrix. When is enough enough? Circulation 108: 1395–1403, 2003

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Bodh I. Jugdutt

  2. Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

    Bodh I. Jugdutt & Grzegorz Sawicki

  3. The Cardiovascular Research Group, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Grzegorz Sawicki

Authors
  1. Bodh I. Jugdutt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grzegorz Sawicki
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s11010-006-9338-9.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jugdutt, B.I., Sawicki, G. AT1receptor blockade alters metabolic, functional and structural proteins after reperfused myocardial infarction: Detection using proteomics. Mol Cell Biochem 263, 179–188 (2004). https://doi.org/10.1023/B:MCBI.0000041860.97991.7a

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:MCBI.0000041860.97991.7a

Search

Navigation