Skip to main content

Advertisement

SpringerLink
Log in

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

  • ORIGINAL ARTICLE
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Here, we have studied the effects of a carbon monoxide-releasing molecule (CORM-3, tricarbonylchloro(glycinato)ruthenium(II)) on acute myocardial ischemia/reperfusion (I/R) injury in hyperglycaemic streptozotocin-treated rats (STZ rats). Occlusion of the left descending coronary artery for 25 min followed by a 2-h reperfusion in STZ-induced hyperglycaemic rats was used as the model. CORM-3 and its inactive counterpart (iCORM-3) were administered 1 h prior to ischemia. The parameters measured included myocardial infarct size (IS) and a selection of inflammatory, oxidative markers and endothelial progenitor cells (CD34+ and CD117/c-kit+). In STZ-induced hyperglycaemic rats, occlusion of the left descending coronary artery caused injury of the myocardial tissue with an IS of ~70%, expressed as fraction of the area at risk. Given intraperitoneally 1 h prior to ischemia, CORM-3 (2–8 mg/kg) afforded significant dose-dependent cardio-protection. Specifically, pre-treatment with CORM-3 reduced infarct size by 14 ± 0.6%, 34 ± 1% and 53 ± 1.6% for doses of 2, 4 and 8 mg/kg, respectively. A negative control (iCORM-3) failed to prevent the cardiac damage induced by I/R. CORM-3 pre-treatment augmented cardiac heme oxygenase-1 (HO-1) protein levels and was associated with an increased number of CD34+- and CD117/c-kit+-positive immunostaining. Modulation of these markers was associated with augmented cardiac eNOS expression and levels of the cytokines TNF-α and IL-1 beta. CORM-3 afforded significant cardio-protection against acute myocardial infarction in STZ-induced hyperglycaemic rats through liberation of small amounts of CO. Of interest, CORM-3 promoted recruitment of the endogenous endothelial progenitor cells within the myocardium, possibly through modulation of cardiac HO-1 and eNOS expression and/or function.

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

Similar content being viewed by others

References

  • Alcaraz MJ, Guillen MI, Ferrandiz ML, Megías J, Motterlini R (2008) Carbon monoxide-releasing molecules: a pharmacological expedient to counteract inflammation. Curr Pharm Des 14:465–472

    Article  PubMed  CAS  Google Scholar 

  • Anantharaman R, Heatley M, Weston CF (2009) Hyperglycaemia in acute coronary syndromes: risk-marker or therapeutic target? Heart 95:697–703

    Article  PubMed  CAS  Google Scholar 

  • Bani-Hani MG, Greenstein D, Mann BE, Green CJ, Motterlini R (2006) A carbon monoxide releasing molecule (CORM-3) attenuates lipopolysaccharide- and interferon-gamma-induced inflammation in microglia. Pharmacol Rep 58:132–144

    PubMed  Google Scholar 

  • Bauersachs J, Widder JD (2008) Endothelial dysfunction in heart failure. Pharmacol Rep 60:119–126

    PubMed  CAS  Google Scholar 

  • Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, Ho PP, Lee LY, Sobel RA, Steinman L, Soares MP (2007) Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J Clin Invest 117:438–447

    Article  PubMed  CAS  Google Scholar 

  • Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, Motterlini R (2003) Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 93:e2–e8

    Article  PubMed  CAS  Google Scholar 

  • D’Amico M, Di Filippo C, La M, Solito E, McLean P, Flower RJ, Oliani SM, Perretti (2000) Lipocortin 1 reduces myocardial ischemia-reperfusion injury by affecting local leukocytes recruitment. FASEB J 14:1867–1869

    PubMed  Google Scholar 

  • Di Filippo C, Cuzzocrea S, Marfella R, Fabbroni V, Scollo G, Berrino L, Giugliano D, Rossi F, D’Amico M (2004) M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart. Eur J Pharmacol 497:65–74

    Article  PubMed  Google Scholar 

  • Di Filippo C, Marfella R, Cuzzocrea S, Piegari E, Petronella P, Giugliano D, Rossi F, D’Amico M (2005) Hyperglycaemia in streptozotocin-induced diabetic rat ncreases infarct size associated with low levels of myocardial HO-1 during ischemia/reperfusion. Diabetes 54:803–810

    Article  PubMed  Google Scholar 

  • Di Filippo C, Cuzzocrea S, Rossi F, Marfella R, D’Amico M (2006) Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev 24:77–87

    Article  PubMed  Google Scholar 

  • Foresti R, Clark JE, Green CJ, Motterlini R (1997) Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J Biol Chem 272:18411–18417

    Article  PubMed  CAS  Google Scholar 

  • Foresti R, Sarathchandra P, Clark JE, Green CJ, Motterlini R (1999) Peroxynitrite induces haem oxygenase-1 in vascular endothelial cells: a link to apoptosis. Biochem J 339:729–736

    Article  PubMed  CAS  Google Scholar 

  • Foresti R, Hammad J, Clark JE, Johnson TR, Mann BE, Friebe A et al (2004) Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br J Pharmacol 142:453–460

    Article  PubMed  CAS  Google Scholar 

  • Guo Y, Stein AB, Wu WJ, Tan W, Zhu X, Li QH, Dawn B, Motterlini R, Bolli R (2004) Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol Heart Circ Physiol 286(5):H1649–H1653

    Article  PubMed  CAS  Google Scholar 

  • Ishii H, Ichimiya S, Kanashiro M, Amano T, Matsubara T, Murohara T (2006) Effects of intravenous nicorandil before reperfusion for acute myocardial infarction in patients with stress hyperglycaemia. Diabetes Care 29:202–206

    Article  PubMed  CAS  Google Scholar 

  • Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436

    Article  PubMed  CAS  Google Scholar 

  • Kohmoto J, Nakao A, Kaizu T, Tsung A, Ikeda A, Tomiyama K, Billiar TR, Choi AM, Murase N, McCurry KR (2006) Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery 140:179–185

    Article  PubMed  Google Scholar 

  • Li TS, Hamano K, Nishida M, Hayashi M, Ito H, Mikamo A, Matsuzaki M (2003) CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation. Am J Physiol Heart Circ Physiol 285:H931–H937

    PubMed  CAS  Google Scholar 

  • Li TS, Hayashi M, Liu ZL, Ito H, Mikamo A, Furutani A, Matsuzaki M, Hamano K (2004) Low angiogenic potency induced by the implantation of ex vivo expanded CD117(+) stem cells. Am J Physiol Heart Circ Physiol 286:H1236–H1241

    Article  PubMed  CAS  Google Scholar 

  • Marfella R, D’Amico M, Di Filippo C, Siniscalchi M, Sasso FC, Ferraraccio F, Rossi F, Paolisso G (2007a) The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes. Cardiovasc Diabetol 6:35

    Article  PubMed  Google Scholar 

  • Marfella R, Di Filippo C, Esposito K, Nappo F, Piegari E, Cuzzocrea S, Berrino L, Rossi F, Giugliano D, D’Amico M (2007b) Absence of inducible nitric oxide synthase reduces myocardial damage during ischemia reperfusion in streptozotocin-induced hyperglycaemic mice. Diabetes 53:454–462

    Article  Google Scholar 

  • Matsumura M, Fukuda N, Kobayashi N, Umezawa H, Takasaka A, Matsumoto T, Yao EH, Ueno T, Negishi N (2009) Effects of atorvastatin on angiogenesis in hindlimb ischemia and endothelial progenitor cell formation in rats. J Atheroscler Thromb 16:319–326

    Article  PubMed  CAS  Google Scholar 

  • Motterlini R (2007) Carbon monoxide-releasing molecules (CO-RMs): vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans 35:1142–1146

    Article  PubMed  CAS  Google Scholar 

  • Musameh MD, Fuller BJ, Mann BE, Green CJ, Motterlini R (2006) Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart. Br J Pharmacol 149:1104–1112

    Article  PubMed  CAS  Google Scholar 

  • Naughton P, Foresti R, Bains SK, Hoque M, Green CJ, Motterlini R (2002) Induction of heme oxygenase 1 by nitrosative stress. A role for nitroxyl anion. J Biol Chem 277:40666–40674

    Article  PubMed  CAS  Google Scholar 

  • Pae HO, Son Y, Kim NH, Jeong HJ, Chang KC, Chung HT (2010) Role of heme oxygenase in preserving vascular bioactive NO. Nitric Oxide 23:251–257

    Article  PubMed  CAS  Google Scholar 

  • Raphael J, Gozal Y, Navot N, Zuo Z (2010) Hyperglycemia inhibits anesthetic-induced postconditioning in the rabbit heart via modulation of phosphatidylinositol-3-kinase/Akt and endothelial nitric oxide synthase signaling. J Cardiovasc Pharmacol 55:348–357

    Article  PubMed  CAS  Google Scholar 

  • Rodella L, Lamon BD, Rezzani R, Sangras B, Goodman AI, Falck JR, Abraham NG (2006) Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes. Free Radic Biol Med 40:2198–2205

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Losada N, Garcia-Pinilla JM, Jimenez-Navarro MF, Gonzalez FJ (2008) Endothelial progenitor cells in cell-based therapy for cardiovascular disease. Cell Mol Biol (Noisy-le-Grand) 54:11–23

    CAS  Google Scholar 

  • Ryter SW, Morse D, Choi AM (2007) Carbon monoxide and bilirubin: potential therapies for pulmonary/vascular injury and disease. Am J Respir Cell Mol Biol 36:175–182

    Article  PubMed  CAS  Google Scholar 

  • Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, Motterlini R (2005) Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol 145:800–810

    Article  PubMed  CAS  Google Scholar 

  • Schober P, Koch A, Zacharowski K, Loer SA (2006) Carbon monoxide: toxic molecule with antiinflammatory and cytoprotective properties. Anasthesiol Intensivmed Notfallmed Schmerzther 41:140–149

    Article  PubMed  CAS  Google Scholar 

  • Schuh A, Liehn EA, Sasse A, Hristov M, Sobota R, Kelm M, Merx MW, Weber C (2008) Transplantation of endothelial progenitor cells improves neovascularization and left ventricular function after myocardial infarction in a rat model. Basic Res Cardiol 103:69–77

    Article  PubMed  Google Scholar 

  • Sekiguchi H, Ii M, Losordo DW (2009) The relative potency and safety of endothelial progenitor cells and unselected mononuclear cells for recovery from myocardial infarction and ischemia. J Cell Physiol 219:235–242

    Article  PubMed  CAS  Google Scholar 

  • Su H, Sun X, Ma H, Zhang HF, Yu QJ, Huang C, Wang XM, Luan RH, Jia GL, Wang HC, Gao F (2007) Acute hyperglycaemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. Am J Physiol Endocrinol Metab 293:629–635

    Article  Google Scholar 

  • Tayem Y, Johnson TR, Mann BE, Green CJ, Motterlini R (2006) Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule. Am J Physiol Renal Physiol 290:F789–F794

    Article  PubMed  CAS  Google Scholar 

  • Undas A, Wiek I, Stêpien E, Zmudka K, Tracz W (2008) Hyperglycaemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care 31:1590–1595

    Article  PubMed  CAS  Google Scholar 

  • Urquhart P, Rosignoli G, Cooper D, Motterlini R, Perretti M (2007) Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J Pharmacol Exp Ther 321:656–662

    Article  PubMed  CAS  Google Scholar 

  • Varadi J, Lekli I, Juhasz B, Bacskay I, Szabo G, Gesztelyi R, Szendrei L, Varga E, Bak I, Foresti R, Motterlini R, Tosaki A (2007) Beneficial effects of carbon monoxide-releasing molecules on post-ischemic myocardial recovery. Life Sci 80:1619–1626

    Article  PubMed  CAS  Google Scholar 

  • Vera T, Henegar JR, Drummond HA, Rimoldi JM, Stec DE (2005) Protective effect of carbon monoxide-releasing compounds in ischemia-induced acute renal failure. J Am Soc Nephrol 16:950–958

    Article  PubMed  CAS  Google Scholar 

  • Wu L, Wang R (2005) Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 57:585–630

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Second University of Naples, Via Costantinopoli 16, 80138, Naples, Italy

    Clara Di Filippo, Francesco Rossi & Michele D’Amico

  2. The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Charterouse Square, London, UK

    Mauro Perretti

  3. Department of Clinical, Public and Preventive Medicine, Second University of Naples, Naples, Italy

    Franca Ferraraccio

  4. INSERM U955 Equipe 3, Faculty of Medicine, University Paris-Est, Creteil, France

    Roberto Motterlini

Authors
  1. Clara Di Filippo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mauro Perretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Franca Ferraraccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberto Motterlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michele D’Amico
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clara Di Filippo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Filippo, C., Perretti, M., Rossi, F. et al. Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3). Naunyn-Schmiedeberg's Arch Pharmacol 385, 137–144 (2012). https://doi.org/10.1007/s00210-011-0703-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-011-0703-1

Keywords

Search

Navigation