Download PDF
Thromb Haemost 2012; 108(03): 464-475
DOI: 10.1160/TH12-05-0303
Theme Issue Article
Schattauer GmbH

Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury

Wojciech Wojakowski
1   Medical University of Silesia, Katowice, Poland
,
Michal Tendera
1   Medical University of Silesia, Katowice, Poland
,
Wieslaw Cybulski
1   Medical University of Silesia, Katowice, Poland
,
Ewa K. Zuba-Surma
2   Department of Cell Biology, Jagiellonian University, Krakow, Poland
,
Krzysztof Szade
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
,
Urszula Florczyk
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
,
Magdalena Kozakowska
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
,
Agnieszka Szymula
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
,
Lukasz Krzych
1   Medical University of Silesia, Katowice, Poland
,
Urszula Paslawska
4   Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
,
Robert Paslawski
5   Medical University, Wroclaw, Poland
,
Krzysztof Milewski
6   American Heart of Poland, Ustron, Poland
,
Piotr P. Buszman
6   American Heart of Poland, Ustron, Poland
,
Edyta Nabialek
1   Medical University of Silesia, Katowice, Poland
,
Waclaw Kuczmik
1   Medical University of Silesia, Katowice, Poland
,
Adrian Janiszewski
7   Wojewódzki Szpital Specjalistyczny, Wroclaw, Poland
,
Piotr Dziegiel
5   Medical University, Wroclaw, Poland
,
Pawel E. Buszman
5   Medical University, Wroclaw, Poland
,
Alicja Józkowicz
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
,
Jozef Dulak
3   Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland
› Author Affiliations
Further Information

Publication History

Received: 10 May 2012

Accepted after minor revision: 10 July 2012

Publication Date:
25 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Heme oxygenase-1 (HO-1) decreases apoptosis, inflammation and oxidative stress. The aim of the study was to investigate the effects of intracoronary infusion of allogenic bone marrow cells (BMC) overexpressing HO-1 in the porcine model of myocardial infarction (MI). MI was produced by balloon occlusion of a coronary artery. BMC were transduced with adenoviruses encoding for HO-1 (HO-1 BMC) or GFP (GFP-BMC) genes. Prior to reperfusion animals received HO-1 BMC, control BMC (unmodified or GFP-BMC) or placebo. Left ventricular (LV) ejection fraction (EF), shortening fraction (SF), end-systolic and enddiastolic diameters (EDD, ESD) were assessed by echocardiography before, 30 minutes (min) and 14 days after reperfusion. BMC significantly improved LVEF and SF early (30 min) after reperfusion as well as after 14 days. Early after reperfusion HO-1 BMC were significantly more effective than control BMC, but after 14 days, there were no differences. There were no effect of cells on LV remodelling and diastolic function. Both HO-1 BMC and control BMC significantly reduced the infarct size vs. placebo (17.2 ± 2.7 and 18.8 ± 2.5, respectively, vs. 27.5 ± 5.1, p= 0.02) in histomorphometry. HO-1-positive donor BMC were detected in the infarct border area in pigs receiving HO-1-cells. No significant differences in expression of inflammatory genes (SDF-1, TNF-α, IL-6, miR21, miR29a and miR133a) in the myocardium were found. In conclusion, intracoronary delivery of allogeneic BMC immediately prior to reperfusion improved the LVEF and reduced the infarct size. HO-1 BMC were not superior to control cells after 14 days, however, produced faster recovery of LVEF. Transplanted cells survived in the peri-infarct zone.

Keywords

Reperfusion - myocardial infarction - bone marrow cells - heme oxygenase-1 - gene therapy
 

  • References

  • 1 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13-20.
    CrossrefPubMedGoogle Scholar
  • 2 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121-1135.
    CrossrefPubMedGoogle Scholar
  • 3 Gerczuk PZ, Kloner RA. An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J Am Coll Cardiol 2012; 59: 969-978.
    CrossrefPubMedGoogle Scholar
  • 4 Clifford DM, Fisher SA, Brunskill SJ. et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2012; 02: CD006536.
    PubMedGoogle Scholar
  • 5 Ratajczak MZ, Kucia M, Jadczyk T. et al. Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?. Leukemia. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 6 Dulak J, Deshane J, Jozkowicz A. et al. Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation 2008; 117: 231-241.
    CrossrefPubMedGoogle Scholar
  • 7 Wu ML, Ho YC, Yet SF. A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal 2011; 15: 1835-1846.
    CrossrefPubMedGoogle Scholar
  • 8 Liu X, Wei J, Peng DH. et al. Absence of heme oxygenase-1 exacerbates myocardial ischemia/reperfusion injury in diabetic mice. Diabetes 2005; 54: 778-784.
    CrossrefPubMedGoogle Scholar
  • 9 Lakkisto P, Palojoki E, Backlund T. et al. Expression of heme oxygenase-1 in response to myocardial infarction in rats. J Mol Cell Cardiol 2002; 34: 1357-1365.
    CrossrefPubMedGoogle Scholar
  • 10 Tang YL, Tang Y, Zhang YC. et al. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol 2005; 46: 1339-1350.
    CrossrefPubMedGoogle Scholar
  • 11 Grochot-Przeczek ALR, Mis J, Skrzypek K. et al. Heme oxygenase-1 accelerates cutaneous wound healing in mice. PLoS ONE 2012; 04: e5803.
    PubMedGoogle Scholar
  • 12 Buszman PP, Wojakowski W, Milewski K. et al. Controlled Reperfusion with Intravenous Bivalirudin and Intracoronary Abciximab Combination Therapy in the Porcine Myocardial Infarction Model. Thromb Res. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 13 Drexler H, Meyer GP, Wollert KC. Bone-marrow-derived cell transfer after ST-elevation myocardial infarction: lessons from the BOOST trial. Nat Clin Pract Cardiovasc Med 2006; 03 (Suppl. 01) S65-68.
    CrossrefPubMedGoogle Scholar
  • 14 Fischer-Rasokat U, Honold J, Seeger FH. et al. Early remodeling processes as predictors of diastolic function 5 years after reperfused acute myocardial infarction and intracoronary progenitor cell application. Clin Res Cardiol 2012; 101: 209-216.
    CrossrefPubMedGoogle Scholar
  • 15 Jiang YB, Zhang XL, Tang YL. et al. Effects of heme oxygenase-1 gene modulated mesenchymal stem cells on vasculogenesis in ischemic swine hearts. Chin Med J (Engl) 2011; 124: 401-407.
    PubMedGoogle Scholar
  • 16 Zeng B, Lin G, Ren X. et al. Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium. J Biomed Sci 2010; 17: 80.
    CrossrefPubMedGoogle Scholar
  • 17 Shu T, Zeng B, Ren X. et al. HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue Cell 2010; 42: 217-222.
    CrossrefPubMedGoogle Scholar
  • 18 Tsubokawa T, Yagi K, Nakanishi C. et al. Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. Am J Physiol Heart Circ Physiol 2010; 298: H1320-1329.
    CrossrefPubMedGoogle Scholar
  • 19 Zeng B, Ren X, Lin G. et al. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement. Cell Biol Int 2008; 32: 1256-1264.
    CrossrefPubMedGoogle Scholar
  • 20 Mullenix PS, Huddleston SJ, Stojadinovic A. et al. A new heart: Somatic stem cells and myocardial regeneration. J Surg Oncol 2012; 105: 475-480.
    CrossrefPubMedGoogle Scholar
  • 21 Hofmann M, Wollert KC, Meyer GP. et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 2005; 111: 2198-2202.
    CrossrefPubMedGoogle Scholar
  • 22 Barbash IM, Chouraqui P, Baron J. et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 2003; 108: 863-868.
    CrossrefPubMedGoogle Scholar
  • 23 Nagaya N, Kangawa K, Itoh T. et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005; 112: 1128-1135.
    CrossrefPubMedGoogle Scholar
  • 24 Li Q, Guo Y, Ou Q. et al. Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV-mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences. Basic Res Cardiol 2011; 106: 1367-1377.
    CrossrefPubMedGoogle Scholar
  • 25 Juhasz B, Varga B, Czompa A. et al. Postischemic cardiac recovery in heme oxygenase-1 transgenic ischemic/reperfused mouse myocardium. J Cell Mol Med 2011; 15: 1973-1982.
    CrossrefPubMedGoogle Scholar
  • 26 Novo G, Cappello F, Rizzo M. et al. Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction. Transl Res 2011; 157: 285-292.
    CrossrefPubMedGoogle Scholar
  • 27 Yang JJ, Yang X, Liu ZQ. et al. Transplantation of adipose tissue-derived stem cells overexpressing heme oxygenase-1 improves functions and remodeling of infarcted myocardium in rabbits. Tohoku J Exp Med 2012; 226: 231-241.
    CrossrefPubMedGoogle Scholar
  • 28 Liu X, Simpson JA, Brunt KR. et al. Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction. Am J Physiol Heart Circ Physiol 2007; 293: H48-59.
    CrossrefPubMedGoogle Scholar
  • 29 Liu X, Pachori AS, Ward CA. et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J 2006; 20: 207-216.
    CrossrefPubMedGoogle Scholar
  • 30 Lakkisto P, Kyto V, Forsten H. et al. Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B. Eur J Pharmacol 2010; 635: 156-164.
    CrossrefPubMedGoogle Scholar
  • 31 Jiang Y, Chen L, Tang Y. et al. HO-1 gene overexpression enhances the beneficial effects of superparamagnetic iron oxide labeled bone marrow stromal cells transplantation in swine hearts underwent ischemia/reperfusion: an MRI study. Basic Res Cardiol 2010; 105: 431-442.
    CrossrefPubMedGoogle Scholar
  • 32 Zeng B, Chen H, Zhu C. et al. Effects of combined mesenchymal stem cells and heme oxygenase-1 therapy on cardiac performance. Eur J Cardiothorac Surg 2008; 34: 850-856.
    CrossrefPubMedGoogle Scholar
  • 33 Lakkisto P, Siren JM, Kyto V. et al. Heme oxygenase-1 induction protects the heart and modulates cellular and extracellular remodelling after myocardial infarction in rats. Exp Biol Med 2011; 236: 1437-1448.
    CrossrefPubMedGoogle Scholar
  • 34 Tuuminen R, Syrjala S, Krebs R. et al. Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection. Circulation 2011; 124: 1138-1150.
    CrossrefPubMedGoogle Scholar
  • 35 Liu SX, Zhang Y, Wang YF. et al. Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A conferring protection from anoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. Int J Cardiol. 2011 epub ahead of print.
    PubMedGoogle Scholar
  • 36 Stein AB, Bolli R, Dawn B. et al. Carbon monoxide induces a late preconditioningmimetic cardioprotective and antiapoptotic milieu in the myocardium. J Mol Cell Cardiol 2012; 52: 228-236.
    CrossrefPubMedGoogle Scholar
  • 37 Wang G, Hamid T, Keith RJ. et al. Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart. Circulation 2010; 121: 1912-1925.
    CrossrefPubMedGoogle Scholar