Abstract 16443: Therapeutic Effect of Prostaglandin D2 Synthase Inhibition in Experimental Autoimmune Myocarditis
Introduction: Myocarditis is a life-threatening inflammatory cardiac disorder. Virus-triggered autoimmunity is considered to play a key role in the progression of myocarditis, however, detailed molecular mechanism still remains unknown.
Prostanoids are arachidonic acid-derived eicosanoids synthesized by cyclooxygenases, prostaglandin (PG) synthase and thromboxane synthase. Prostanoids play essential roles in regulation of vascular homeostasis and in various cardiovascular diseases. In the present study, we investigated the role of prostanoids in the pathogenesis of myocarditis using experimental autoimmune myocarditis (EAM) model mice.
Methods and Results: We first analyzed the level of eicosanoids and the expression level of their synthases in the heart of EAM model mice. EAM model mice were generated by immunization of the male BALB/c mice with alpha-MHC peptide emulsified with a complete Freund’s adjuvant. We identified that the level of PGD2 and the expression of hematopoietic PGD2 synthase (HPGDS) were increased in the heart of EAM model mice, suggesting the involvement of PGD2 in the pathogenesis of experimental myocarditis. To test the role of HPGDS in the progression of myocarditis in EAM model mice, we treated the EAM model mice with TFC-007 (30 mg/Kg), a selective HPGDS inhibitor, and assessed the severity of myocarditis by echocardiography and picrosirius red staining. Treatment with TFC-007 decreased the content of PGD2 in the heart (9.2±0.29 pg/mg tissue weight (control) vs. 1.7±1.3 (TFC-007). P=0.004) suggesting that HPGDS is the major PGD2 synthase that play a role in myocarditis. Echocardiographic analysis revealed that left ventricular wall thickness was improved by TFC-007 treatment (1.40±0.04mm (control) vs. 1.27±0.05 (TFC-007). P=0.04). Fibrotic area was also reduced by TFC-007 treatment (9.9±1.3% (control) vs. 6.8±1.0% (TFC-007). P=0.04).
Conclusions: Our findings suggest that cardiac PGD2 plays an important role in the progression of myocarditis in EAM model mice. Inhibition of HPGDS might become a novel therapeutic target in patients with myocarditis.
Author Disclosures: T. Yamaguchi: None. Y. Motozawa: None. H. Kumagai: None. M. Shinohara: None. Y. Ikeda: None. I. Manabe: None. K. Aritake: None. Y. Urade: None. I. Komuro: None.
- © 2016 by American Heart Association, Inc.