Abstract 13017: Administration of Intramyocardial Chemokine Induce Myocardial Recovery by Modulating the Acute Inflammatory Response to Ischemia

Abstract

Introduction: We have previously shown that the exogenously injected chemokines induce robust myocardial recovery and angiogenesis after a myocardial infarction (MI). Angiogenesis, however, is a late response, and the acute cellular drivers of chemokine induced recovery remain elusive. Recently it has been shown that an acute macrophage response is central to post-MI recovery after stem-cell injections. As many chemokines act as immunomodulators, we hypothesized that both angiogenic chemokines (SDF-1) and non-angiogenic chemokines of viral origin (vMIP-II) can similarly elicit a macrophage response. Methods: MI was surgically induced in 39 male and female C57BL/6 mice (6-8 weeks old) by ligation of the left anterior descending coronary artery. Mice were randomly assigned to receive intramyocardial injections of PBS (saline), SDF-1, or vMIP-II. Two hearts from each treatment group were explanted at post-operative day 3 (P3) for single cell suspension preparation. Viable cells were used for single cell RNA sequencing (scRNAseq). Echocardiography was performed for all remaining mice at P7 to assess for functional recovery, and hearts were explanted for histology at P14. Results: Treatment with both SDF-1 and vMIP-II led to significant functional recovery assessed via echocardiography at P7, one week in advance of arteriolar collateralization (Ejection Fraction 0.38 ± 0.14 and 0.50 ± 0.15 in SDF-1 and vMIP respectively; 0.27 ± 0.13 in PBS; t-test adjusted p = 0.023). scRNAseq of 7918 captured cells showed a robust acute inflammatory macrophage response at P3 across treatment groups. A robust expansion of Arginase-1 (Arg1+) macrophages - a known M2 anti-inflammatory subtype - was seen specifically in chemokine treated mice at P3 (9% in PBS vs 16.5% in both SDF-1 and vMIP-II). Conclusions: We show that vMIP-II triggers myocardial recovery similar to SDF-1. Furthermore, we show a robust and consistent Arg1+ macrophage response present in both treatment groups.