Details

Autor(en) / Beteiligte

• Ito, Shogo
• Yuasa, Shinsuke
• Komuro, Jin
• Katsuki, Toshiomi
• Kimura, Mai
• Kishino, Yoshikazu
• Kusumoto, Dai
• Hashimoto, Hisayuki
• Fukumoto, Yoshihiro
• Fukuda, Keiichi

Titel

Abstract 835: Development of Molecular Targeted Therapy Against Right Ventricular Failure: Evaluation by Transcriptome and i n vivo Analysis

Ist Teil von

• Circulation research, 2019-08, Vol.125 (Suppl_1)

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract only Backgrounds: Right ventricular (RV) failure is a final common pathway in heart failure. But there is no specific therapy for RV failure. Moreover, it remains unclear how RV failure is developed. To develop a novel therapy for RV failure, we focused on the RV specific character and elucidate the function in RV failure. 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 rat cardiomyocytes in vitro. To understand the function of target molecule in vivo, we induced RV failure by pulmonary artery constriction (PAC) in mice and the pathway was specifically blocked in the RV failure model. Results: In microarray analysis for upper RV, RV free wall, LV and ventricular septum, 995 genes were statistically extracted as DEG in upper RV. An alternative complement pathway was significantly activated in upper RV and complement factor, and C3a was a potential upstream factor attributable to unique feature of upper RV. Because C3a plays a central role in alternative complement pathway, we examined the direct role of C3a in cardiomyocytes and RV function. Administration of C3a recombinant protein to primary-cultured cardiomyocytes activated the several MAP kinases including ERK, p38 and JNK, via C3a receptor. Mice developed severe RV failure around 14 days after PAC. Surprisingly, administration of C3a receptor antagonist dramatically improved right ventricular contractile dysfunction in PAC mice. C3 (substrate of C3a) deficient PAC mice also attenuated RV contractile dysfunction, fibrotic change and fetal gene expressions. There results indicated that complement factor C3a regulates the unique phenotypes in RV. Chemical or genetical blockade of C3a ameliorates RV dysfunction in PAC mice. Conclusion: We revealed that alternative complement pathway was activated in RV and C3a had a crucial role in the pathogenesis of RV failure. Accordingly, the blockade of C3a pathway would be a potential therapeutic target for RV disorders.