Abstract 20536: Cardiomyocyte Derived D-dopachrome Tautomerase Protects Against Heart Failure
Left ventricular hypertrophy (LVH) is common in cardiovascular disease and predisposes to heart failure, however, the molecular mechanisms modulating the transition of LVH to heart failure remain incompletely understood. D-dopachrome tautomerase (DDT) is a novel protein that is highly expressed in cardiomyocytes and is a functional homolog of the macrophage migration inhibitory factor (MIF). It binds to the CD74 receptor and has an autocrine-paracrine cardioprotective effect during ischemia. However, whether DDT has a protective effect during pressure overload induced heart failure is unclear. Thus, we investigated the role of endogenous DDT in cardiomyocyte-specific DDT knockout (KO) mice (MHC-Cre Ddtfl/fl) and littermate (Ddtfl/fl) controls (CON) subjected to transverse aortic constriction (TAC) or sham surgery (n=12-16 per group). Cardiac function was evaluated serially by echocardiography and hearts were analyzed at 1 and 7 weeks for histology and molecular studies. There were no functional differences in KO and CON mice at baseline or after sham surgery. Compared to CON, KO mice developed similar LV wall thickening, but much more rapid LV dilatation and decreased LVEF, detectable as early as 2 weeks after TAC. At 7 weeks after TAC, LVEF was decreased by 45%, LV inner diameter increased by 11% and LV mass increased by 28% compare in KO vs. CON (all P<0.05). KO hearts had increased apoptosis, decreased capillary density and increased fibrosis at 7 weeks after TAC, compared to CON (p<0.05). Cardiomyocyte cross-sectional area was similar in the two groups after TAC. KO hearts had reduced Vegfa (0.65 fold), Vegfb (0.55 fold) mRNA transcripts and enhanced CTGF (2.5 fold), Col1a1 (1.8 fold) transcripts 1 week after TAC. In addition, recombinant DDT (rDDT) had a pro-angiogenic function to stimulate endothelial cells (HUVEC) matrigel tube formation by activating Erk and Akt signaling (p<0.05), as well as an anti-fibrotic effect to inhibit TGFβ-induced Smad-2 phosphorylation in fibroblast (NIH3T3) cells. Thus, cardiomyocyte-derived DDT prevents the transition from compensated hypertrophy to contractile dysfunction and heart failure during pressure overload, potentially through novel pro-angiogenic and anti-fibrotic paracrine effects.
Author Disclosures: Y. Ma: None. K.N. Su: None. J. Zhang: None. D. Pfau: None. X. Wu: None. X. Hu: None. R. Bucala: None. L. Young: None.
- © 2016 by American Heart Association, Inc.