Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury

JACC Basic Transl Sci. 2021 Aug 23;6(8):631-646. doi: 10.1016/j.jacbts.2021.07.001. eCollection 2021 Aug.

Abstract

The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that CLEC4E expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. CLEC4E expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of Clec4e signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in Clec4e -/- translates into significantly improved LV structural and functional remodeling at 4 weeks' follow-up. The early transcriptome of LV tissue from Clec4e -/- mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting CLEC4E in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury.

Keywords: ACS, acute coronary syndrome; AMI, acute myocardial infarction; ANOVA, analysis of variance; CAD, coronary artery disease; CLEC4E; CLEC4E, C-type lectin domain family 4 member E; CMC, cardiac myocyte; Car3, carbonic anhydrase 3; Cxcl2, CXC chemokine ligand 2; Cxcr2, CXC chemokine receptor 2; DAMP, damage-associated molecular pattern; ECM, extracellular matrix; ESV, end-systolic volume; Efna2, ephrin A2; Grk2, G protein–coupled receptor kinase 2; I/R, ischemia-reperfusion; LAD, left anterior descending coronary artery; LV, left ventricular; MPO, myeloperoxidase; MRI, magnetic resonance imaging; NS, not significant; PRR, pattern recognition receptor; RNA, ribonucleic acid; SMC, smooth muscle cell; STEMI, ST-segment elevation myocardial infarction; TnT, troponin T; WT, wild-type; hs-TnI, high-sensitivity troponin I; inflammation; ischemia-reperfusion injury; magnetic resonance imaging; myocardial remodeling; qRT-PCR, quantitative reverse transcription polymerase chain reaction.