IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction

Meijing Wang, Jiangning Tan, Yue Wang, Kirstan K. Meldrum, Charles A. Dinarello, Daniel R. Meldrum

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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 ± 9.47 mmHg compared to 59.3 ± 7.8 mmHg in wild-type MSCs and 37.8 ± 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 ± 1.76% versus wild-type MSCs (57.4 ± 1.33%) and vehicle (39.2 ± 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 ± 2.16% compared to 46.4 ± 1.92% in wild-type MSCs and 60.7 ± 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.

Original languageEnglish
Pages (from-to)17499-17504
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number41
DOIs
StatePublished - Oct 13 2009

Fingerprint

Mesenchymal Stromal Cells
Infarction
Ischemia
Interleukin-18
Vascular Endothelial Growth Factor A
Wounds and Injuries
interleukin-18 binding protein
Cell Death
Stem Cells
Inflammation
Ventricular Remodeling
Ventricular Pressure
Stroke Volume
Transgenic Mice
Myocardial Ischemia
Ligation
Interleukin-6
Coronary Vessels
Myocardial Infarction
Cytokines

Keywords

  • IL-1 family
  • Inflammation
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • General

Cite this

IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. / Wang, Meijing; Tan, Jiangning; Wang, Yue; Meldrum, Kirstan K.; Dinarello, Charles A.; Meldrum, Daniel R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 41, 13.10.2009, p. 17499-17504.

Research output: Contribution to journalArticle

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abstract = "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 ± 9.47 mmHg compared to 59.3 ± 7.8 mmHg in wild-type MSCs and 37.8 ± 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 ± 1.76{\%} versus wild-type MSCs (57.4 ± 1.33{\%}) and vehicle (39.2 ± 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 ± 2.16{\%} compared to 46.4 ± 1.92{\%} in wild-type MSCs and 60.7 ± 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.",
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