Abstract 11441: Inhibition of Prolyl Hydroxylase Domain-Containing Protein Promoted Neovascularization and Ameliorated Cardiac Dysfunction in Experimental Autoimmune Myocarditis in Mice
Introduction: Mechanisms of cardiac dysfunction in myocarditis have not been fully elucidated.Though it remains controversial whether angiogenesis is beneficial or harmful in inflammatory disease, significant vascular destruction might possibly impair cardiac function in myocarditis. The prolyl hydroxylase domain-containing protein (PHD) inhibitor is a potential drug to promote angiogenesis as it stabilizes hypoxia inducible transcription factor (HIF). The effects of PHD inhibitor on myocarditis have not been studied.
Objective: We examined whether the PHD inhibitor TM6008 could affect cardiac function in experimental autoimmune myocarditis (EAM) by promoting angiogenesis.
Methods and Results: EAM was induced on BALB/c mice by immunizing them with synthesized alpha myosin heavy chain peptide on day 0 and 7. 200mg/kg of TM6008 (TM6008 group) or vehicle (control group) was administered orally every day. Echocardiography revealed TM6008 improved left ventricular ejection fraction (LVEF) significantly [LVEF: 68.1±1.8% in control group, 78.1±2.0% in TM6008 group (P<0.01, n=8 in each group)]. Though TM6008 did not affect the severity of myocardial cell infiltration on the 21st day of EAM [affected area:23.0±9.6% in control group, 19.3±10.9% in TM6008 group], it tended to reduce the cardiac fibrosis [fibrotic area: 11.0±4.8% in control group, 4.1±1.7% in TM 6008 group (not significant)]. Immunohistochemistry showed that CD31-positive blood vessels were significantly preserved in the TM6008 group compared to the control group [vascular number/ cross sectional area: 0.19±0.04 in control group, 0.32±0.11 in TM6008 group (P=0.03, n=8 in each group)]. Immunoblotting revealed that TM6008 increased expression of HIF-1alpha (trend), HIF-2alpha (P=0.02) and vascular endothelial growth factor (P=0.01) in myocardial tissues on the 15th day of EAM (n=5 in control group, n=4 in TM6008 group).
Conclusion: The prolyl hydroxylase domain-containing protein inhibitor (TM6008) could ameliorate cardiac dysfunction in EAM, partially through promoting neovascularization. Relief of tissue hypoxia via neovascularization could be beneficial in the improvement of cardiac function in myocarditis.
- © 2013 by American Heart Association, Inc.