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

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.

• Authors: 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
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 118 Issue 1 Pg. 267-281 (01 07 2022) ISSN: 1755-3245 [Electronic] England
• PMID: 33125066 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected].

Chemical References

• Anti-Inflammatory Agents
• E-Selectin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cell Adhesion (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• E-Selectin (metabolism)
• Endothelial Cells (drug effects, immunology, metabolism, pathology)
• Female
• Fibrosis
• Humans
• Male
• Mice, Inbred C57BL
• Myocardial Infarction (immunology, metabolism, pathology, prevention & control)
• Myocardial Reperfusion Injury (immunology, metabolism, pathology, prevention & control)
• Myocardium (immunology, metabolism, pathology)
• Neutrophil Activation (drug effects)
• Neutrophil Infiltration (drug effects)
• Neutrophils (drug effects, immunology, metabolism)
• Platelet Activation (drug effects)
• Signal Transduction
• Mice