Abstract 317: Conditional Knockout Of Phd2 Ameliorates High-fat Diet-induced Cardiac Dysfunction Via Inhibition Of Tlr4-nfκB Pathway In A Hifa-independent Manner

Abstract

Oxygen sensors prolyl hydroxylases (PHDs) plays an important role in the regulation of hypoxia-inducible factor (HIFα) as well as nuclear factor-κ B (NF-κB) activity. Our previous study demonstrated that activation of vascular Toll-like receptor TLR-MyD88-IRAK4 signaling pathway contributes to vascular dysfunction in high-fat-diet (HFD)-induced diabetes. The present study investigates whether conditional knockout of prolyl hydroxylase-2 (PHD2) improves cardiac function via suppression of TLR-NF-κb signaling in a HFD-induced diabetic cardiomyopathy mouse model. Wild type (WT-Cre + ), PHD2 conditional knockout (PHD2CKO) and PHD2 +/- mice were fed with either HFD or normal chow diet (NFD) for 18 weeks. The levels of PHD1-3, HIF, angiogenic growth factors, MyD88, IRAK-4, TLR4, NF-κb and Wnt7b gene expression were measured. Cardiac hypertrophy, fibrosis and cardiac function were analyzed at 18 weeks after PHD2 deactivation . Feeding of WT-Cre + mice with HFD for 18 weeks resulted in a significant reduction of cardiac functions. The basal expression of PHD2 was significantly increased in the heart of HFD mice. The expression of PHD2 was significantly reduced in the heart of PHD2CKO and PHD2 +/- mice fed with HFD whereas PHD1 and PHD3 expression remains unchanged. Conditional knockout of PHD2 resulted in suppression of MyD88, IRAK-4, TLR4, NF-κb and Wnt7b expression. Deactivation of PHD2 had little effect on the expression of HIF1α, HIF2α and angiogenic growth factor in the hearts of HFD-induced diabetic mice. Conditional knockout of PHD2 further suppressed HFD-induced cardiac hypertrophy and significantly improved HFD-induced cardiac dysfunction. In contrast, conditional knockout of PHD2 resulted in an increase in HIFα expression and cardiac dysfunction in NFD mice. These results suggest that deactivation of PHD2 attenuates HFD-induced diabetic cardiomyopathy via suppression of TLR4-MyD88-IRAK4-NF-κb-Wnt7b signaling pathway in a HIF-independent manner.