Abstract 264: A Complement Pathway is Responsible for Degeneration of Right Ventricular Outflow Tract

Abstract

Backgrounds: Right ventricular outflow tract (RVOT) has a unique role in the pathogenesis of inherited cardiac diseases such as Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy. However, it remains elusive how RVOT plays a role in the pathogenesis. We hypothesized that RVOT would have different character from other parts of the heart and those phenotypes would be regulated by key factors. Methods: Microarray analysis of several parts of adult murine hearts was performed and differentially expressed genes (DEGs) in RVOT were extracted. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Potential upstream candidate genes were examined using rat cardiomyocytes in vitro and adult mouse in vivo. Results: As a result of microarray analysis for RVOT, right ventricle, left ventricle and ventricular septum, 995 genes were statistically extracted as DEG in RVOT. IPA analysis revealed that an alternative complement pathway was significantly activated in RVOT. Additionally, complement factor, C3a was shown as a potential upstream gene attributable to these features. Administration of C3a protein to cardiomyocytes resulted in activation of several MAP kinases including ERK via C3a receptor and suppression of oncostatin M signaling. Furthermore, in vivo analysis, administration of C3a receptor antagonist dramatically improved right ventricular function in mouse model of right ventricular overload, pulmonary artery constriction. There results indicated that C3a would regulate the unique phenotypes in RVOT and would be the potent effector to right ventricular heart failure. Conclusion: We revealed that an activated alternative complement pathway has a crucial role in the unique features of RVOT and the pathogenesis of right ventricular heart failure. The blockade of the pathway would be a therapeutic target of RVOT-related diseases.