Targeting E-Selectin Impairs Cardiac Function After Myocardial Infarction

Background and Objectives: Regulation of excessive inflammation after MI is a promising therapeutic target. E-selectin, a cell adhesion molecule expressed on activated endothelial cells, promotes attachment of inflammatory cells. We aimed to determine whether a new N-(2-hydroxypropyl) methacrylamide-based E-selectin binding co-polymer (P-ESBP) could target the ischemic myocardium, as well as examine the therapeutic potential of E-selectin inhibition using these co-polymers.

Methods and Results: To test the targeting of P-ESBP, ischemia/reperfusion was induced in BalbC female mice by transient (45`) occlusion of the LAD. Four hours later, we injected either P-ESBP copolymer marked by Rhodamin (n=2), a marked co-polymer without ESBP (n=2) or saline (n=1). Eighteen hours after injections, hearts were examined for histological analysis, and showed specific targeting of P-ESBP to the re-perfused myocardium. To test for therapeutic effect: ischemia (45`) and reperfusion were induced in APOE-/- atherosclerotic male and female mice. Four hours later, animals were randomized to either IV injection of P-ESBP co-polymers (n=10) or saline (n=12). Cardiac remodeling and function were evaluated by echocardiography at 4 hours and 7 days after reperfusion. We found no apparent differences in cardiac remodeling and function between the mixed sex groups. However, additional analysis revealed that male mice had improved LVEF compared with female mice, in both saline and P-ESBP-treated groups (p=0.06, p=0.34). Subgroup analysis of males only (n=12) revealed a trend towards harmful effects of P-ESBP on cardiac recovery from ischemic injury (EF: baseline p=0.57 and day 7, p=0.095). Finally, we evaluated the scars by postmortem histology (day 8), and found that mid-ventricular scar was more common in the P-ESBP (9/10) than in the saline (7/12) group (p=0.16).

Conclusions: P-ESBP copolymer effectively targets the ischemic myocardium, but tends to impair recovery and function after myocardial injury. Our findings highlight the essential role of inflammation in infarct healing, regeneration and repair.