Research article summary (published 23 Sep 2009):

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

Full 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 + 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.

Author information

Author/s: Wang, Meijing (M); Tan, Jiangning (J); Wang, Yue (Y); Meldrum, Kirstan K (KK); Dinarello, Charles A (CA); Meldrum, Daniel R (DR);

Affiliation: Department of Surgery, Methodist Hospital, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

Grants: K08DK065892 (Agency:NIDDK NIH HHS) ; K99/R00 HL0876077 (Agency:NHLBI NIH HHS) ; R01AI015614 (Agency:NIAID NIH HHS) ; R01GM070628 (Agency:NIGMS NIH HHS) ; R01HL085595 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A), published in United States. (Language: eng)

Reference: 2009-Oct; vol 106 (issue 41) : pp 17499-504

Dates: Created 2009/10/15; Completed 2009/11/03;

PMID: 19805173, status: MEDLINE (last retrieved date: 11/3/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Cell Division Cells, Cultured Down-Regulation Female Heart - drug effects; physiopathology Humans Intercellular Signaling Peptides and Proteins - therapeutic use Interleukin-18 - therapeutic use

Interleukin-18 - therapeutic use Mesenchymal Stem Cells - cytology; pathology; physiology Mice Myocardial Infarction - prevention & control Myocardial Ischemia - prevention & control Myocardial Perfusion Imaging Rats Tumor Necrosis Factor-alpha - pharmacology Vascular Endothelial Growth Factor A - genetics; physiology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Intercellular Signaling Peptides and Proteins (0) ; Interleukin-18 (0) ; Tumor Necrosis Factor-alpha (0) ; Vascular Endothelial Growth Factor A (0) ; interleukin-18 binding protein (0)

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