IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction.
IL-18 is a proinflammatory cytokine known to cause tissue injury by inducing inflammation and cell death. Increased levels of IL-18 are associated with myocardial injury after ischemia or infarction. IL-18-binding protein (IL-18BP), the naturally occurring inhibitor of IL-18 activity, decreases the severity of inflammation in response to injury. In the present study, mesenchymal stem cells (MSCs) derived from mice transgenic for over expression of human IL-18BP were tested in rat models of global myocardial ischemia and acute myocardial infarction. Improved myocardial function is associated with production of VEGF, and in vitro, IL-18BP MSCs secreted higher levels of constitutive VEGF compared to wild-type MSCs. Whereas IL-18 increased cell death and reduced VEGF in wild-type MSCs, IL-18BP MSCs were protected. In an isolated heart model, intracoronary infusion of IL-18BP MSCs before ischemia increased postischemic left ventricular (LV) developed pressure to 79.5 + or - 9.47 mmHg compared to 59.3 + or - 7.8 mmHg in wild-type MSCs and 37.8 + or - 5 mmHg in the vehicle group. Similarly, using a coronary artery ligation model, intramyocardial injection of IL-18BP MSCs improved LV ejection fraction to 67.8 + or - 1.76% versus wild-type MSCs (57.4 + or - 1.33%) and vehicle (39.2 + or - 2.07%), increased LV fractional shortening 1.25-fold over wild-type MSCs and 1.95-fold over vehicle, decreased infarct size to 38.8 + or - 2.16% compared to 46.4 + or - 1.92% in wild-type MSCs and 60.7 + or - 2.2% in vehicle, reduced adverse ventricular remodeling, increased myocardial VEGF production, and decreased IL-6 levels. This study provides the concept that IL-18BP genetically modified stem cells improve cardioprotection over that observed with unmodified stem cells.
Wang
Meijing
M
Department of Surgery, Methodist Hospital, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Tan
Jiangning
J
Wang
Yue
Y
Meldrum
Kirstan K
KK
Dinarello
Charles A
CA
Meldrum
Daniel R
DR
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000627:therapeutic use*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000517:prevention & control*; D055414:Myocardial Perfusion Imaging; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C118370:interleukin-18 binding protein