(852.1) Nexinhib20 prevents myocardial ischemia-reperfusion injury by inhibiting neutrophil adhesion and β2 integrin activation

Poster Board Number: E65

Zhichao Fan (UConn Health, UConn Health), Wei Liu (UConn Health), Chunxia Cronin (UConn Health), Chengliang Wang (UConn Health), Jianbin Ruan (UConn Health), Jennifer Johnson (The Scripps Research Institute), Sergio Catz (The Scripps Research Institute), Hao Sun (University of California San Diego), Alex Groisman (University of California San Diego), Yunfeng Chen (The Scripps Research Institute), Liang Hu (the First Affiliated Hospital of Zhengzhou University), Anthony Vella (UConn Health), Bruce Liang (UConn Health)

Primary percutaneous coronary intervention (PPCI)—a therapy intended to restore blood flow after acute myocardial infarction—can also induce myocardial ischemia-reperfusion (I/R) injury, exacerbating cardiomyocyte death. Neutrophil-mediated cardiac tissue damage contributes prominently to the process of myocardial I/R injury. Therefore, limiting neutrophil recruitment and exocytosis may prevent myocardial I/R injury after PPCI. Here, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits both neutrophil adhesion and exocytosis and prevents myocardial I/R injury in a mouse model. Using a microfluidic chamber, we found that Nexinhib20 inhibited interleukin 8 (IL-8)-induced β2 integrin-dependent human neutrophil adhesion under flow. Using dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 integrin activation after IL-8 stimulation. Western blots of Rac-1-GTP pull-down assay confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. In vitro competing assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.

This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454, R41HL156322, R44HL152710, and K99HL153678), a Career Development Award from American Heart Association (18CDA34110426), and a startup fund from UConn Health.