Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor κB (NF-κB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFβ1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.
Highlights
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C [MIM: 107970]) is a dominantly genetic disease of cardiac muscle with high risk of sudden cardiac death and heart failure
Since transmembrane protein 43 (TMEM43) S358L mutation is ubiquitously identified in ARVD5 patients, we generated TMEM43 S358L knock-in (KI) mice by homologous recombination-mediated genomic targeting (Fig. 1A)
ARVD is a dominantly genetic defect with much higher risk in young male persons. According to this feature of ARVD, we examined heterozygous TMEM43 S358L-KI mice of adult males that contain one allele of S358L mutation
Summary
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C [MIM: 107970]) is a dominantly genetic disease of cardiac muscle with high risk of sudden cardiac death and heart failure. The prevalence of this disease in general population is about 1:5,000. The occurring rate in male is higher than that in female (Muthappan and Calkins, 2008; Pilichou et al, 2011). ARVD is characterized by progressively fibrofatty replacement of heart muscle mainly in the right ventricular myocardium, leading to ventricular arrhythmias and structural abnormalities. TMEM43 is associated with ARVD5 [MIM: 604400], a highly lethal and fully penetrant ARVD subtype (Lombardi et al, 2011; Muthappan and Calkins, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
