Selectin-targeting glycosaminoglycan-peptide conjugate limits neutrophil-mediated cardiac reperfusion injury

Tima Dehghani, Phung N. Thai, Harkanwalpreet Sodhi, Lu Ren, Padmini Sirish, Carol E. Nader, Valeriy Timofeyev, James L. Overton, Xiaocen Li, Kit S. Lam, Nipavan Chiamvimonvat, Alyssa Panitch

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

AIMS: One of the hallmarks of myocardial infarction (MI) is excessive inflammation. During an inflammatory insult, damaged endothelial cells shed their glycocalyx, a carbohydrate-rich layer on the cell surface which provides a regulatory interface to immune cell adhesion. Selectin-mediated neutrophilia occurs as a result of endothelial injury and inflammation. We recently designed a novel selectin-targeting glycocalyx mimetic (termed DS-IkL) capable of binding inflamed endothelial cells. This study examines the capacity of DS-IkL to limit neutrophil binding and platelet activation on inflamed endothelial cells, as well as the cardioprotective effects of DS-IkL after acute myocardial infarction. METHODS AND RESULTS: In vitro, DS-IkL diminished neutrophil interactions with both recombinant selectin and inflamed endothelial cells, and limited platelet activation on inflamed endothelial cells. Our data demonstrated that DS-IkL localized to regions of vascular inflammation in vivo after 45 min of left anterior descending coronary artery ligation-induced MI. Further, findings from this study show DS-IkL treatment had short- and long-term cardioprotective effects after ischaemia/reperfusion of the left anterior descending coronary artery. Mice treated with DS-IkL immediately after ischaemia/reperfusion and 24 h later exhibited reduced neutrophil extravasation, macrophage accumulation, fibroblast and endothelial cell proliferation, and fibrosis compared to saline controls. CONCLUSIONS: Our findings suggest that DS-IkL has great therapeutic potential after MI by limiting reperfusion injury induced by the immune response.

Original languageEnglish (US)
Pages (from-to)267-281
Number of pages15
JournalCardiovascular research
Volume118
Issue number1
DOIs
StatePublished - Jan 7 2022
Externally publishedYes

Keywords

  • Endothelial cell dysfunction
  • Fibrosis
  • Glycocalyx
  • Inflammation
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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