Abstract 875: Cardiomyocyte Derived DDT Protects Against Myocardial Infarction Induced Heart Failure

Background: D-dopachrome tautomerase (DDT), the only homolog of macrophage migration inhibitory factor (MIF), is a cytokine highly expressed in cardiomyocytes and has autocrine-paracrine effects, signaling through the CD74 receptor. Endogenous DDT and MIF prevent ischemia-reperfusion injury in mice. In this study, we investigated whether endogenous cardiomyocyte DDT protects against myocardial remodeling and heart failure after myocardial infarction. Methods: Cardiomyocyte-specific DDT knockout (cKO) and littermate control (CON) mice underwent myocardial infarction (MI) or sham surgery. Serial echocardiography was performed at baseline, 1 day before permanent coronary ligation and 1 day, 1 week, and 4 weeks after MI or sham surgery. Hearts were analyzed at 3 days after MI or sham surgery for histology and molecular studies. Results: No baseline differences in left ventricular (LV) function were observed in cKO and CON mice at baseline or after sham surgery. The initial infarction sizes were comparable at 1 day after coronary ligation in cKO and CON. Compared to CON, cKO mice developed more rapid LV dilatation, and decreased LV ejection fraction (EF) and stroke volume (SV) as early as 1 week after MI. At 4 weeks after MI, LVEF was 33% lower and SV lower by 43% in cKO vs. CON (n=4-5/group, all P<0.01). Hemodynamic analysis showed that LV end diastolic pressure in the cKO mice was 38% higher in cKO vs. CON after 4 weeks MI (p=0.052). Immunoblots showed diminished phosphorylation of AMPK and downstream ACC in the cKO mice 3 days after MI. Immunohistochemistry staining with CD3 and F4/80 staining showed increased T cells and macrophage cells in the cKO mice 3 days after MI (p<0.05). We further assessed the regulation of cardiac DDT expression in chronic human heart failure. In hearts explanted from patients with advanced heart failure during transplantation for ischemic cardiomyopathy (n=8), DDT mRNA and protein expression were also reduced by 40% and 58% compared to controls (P<0.01). Conclusion: Cardiomyocyte-derived DDT prevents adverse cardiac remodeling after MI, potentially through AMPK signaling and anti-inflammatory effects. Down-regulation of cardiac DDT may contribute to pathogenesis of advanced heart failure.