Abstract P3061: Development Of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement In Complement C3- Factor D- C3a Pathway

• Published in: Circulation research 2023-08, Vol.133 (Suppl_1)
• Main Authors: Ito, Shogo, Yuasa, Shinsuke, YAMAKAWA, Hiroyuki, Komuro, Jin, Hashimoto, Hisayuki, Kimura, Mai, Nakao, Eichi, Fukuda, Keiichi, Fukumoto, Yoshihiro
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.133.suppl_1.P3061

Abstract only Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on RV specific pathway. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis. Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro. To understand the function of target molecule in vivo, we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using RV failure model. Results: In microarray analysis elucidated 995 genes as DEGs in RV. Pathway analysis showed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to primary cultured ventricular myocyte indicated that phosphorylation of several MAP kinases were enhanced. In vivo, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study showed that RV fibrosis was significantly suppressed. In wild type mice with PAC, administration of C3a receptor antagonist dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Furthermore, electrophysiological analysis by isolated cardiomyocyte showed that calcium overload was also attenuated in RV cardiomyocyte of C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV and chemical or genetical blockade of C3a ameliorates RV dysfunction and RV fibrosis in PAC mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating cardiac function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target to RV failure.