Abstract
Patient studies show that chitinase 3-like 1 (CHI3L1) is a novel biomarker of coronary artery disease (CAD). Furthermore, CHI3L1 plasma level is a strong predictor of all-cause of mortality in patients with CAD, and is a strong indicator of heart failure progression. Studies from our lab revealed that CHI3L1 is elevated in hearts after MI, and systemic administration of CHI3L1 in mice exacerbated post-MI fibrosis and left ventricular dysfunction. The goal of the current study was to delineate the mechanism of CHI3L1 secretion after MI and test the impact of CHI3L1 on post-MI replacement fibrosis. We found that CHI3L1 levels were rapidly increased in infarcted regions of LV at 2 d after MI and remained significantly elevated at 7 and 35 d (n=5-11/group, p<0.05). More detailed analysis revealed that neutrophils are the main source of CHI3L1. Protein CHI3L1 expression in neutrophils was 3-4 orders of magnitude higher compared with cardiac fibroblasts, macrophages, endothelial cells, and cardiomyocytes (n=3-5, p<0.0001). Next, we found that Chil1 -/- subjected to permanent coronary artery ligation showed decreased end-systolic and diastolic volumes and increased ejection fraction measured at 7 and 35 d with echocardiography (n=7-10/group, p<0.05 at 7 d; n=16-20/group, p<0.05 at 35 d). Histological analysis of hearts displayed no change in scar size but left ventricular expansion index was reduced and the infarcted wall thickness was increased in Chil1 -/- mice compared to their Chil1 +/+ controls (n=16-18/group, p<0.01). We found no difference in cardiomyocyte cross-sectional area (WGA staining) and capillary density (isolectin B4 staining). These data provide proof of principle evidence that CHI3L1 is a neutrophil secreted factor that has an adverse effect on replacement fibrosis after MI. Future efforts will focus on the mechanism of actions of CHI3L1 and the identification of strategies to inhibit detrimental actions of CHI3L1 on replacement fibrosis and heart failure.
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