Dr. Guey-Shin Wang, Dr. Ching-Feng Cheng and colleagues at the Institute of Biomedical Sciences, Academia Sinica uncovered a novel mechanism of connexin 43 reduction in dilated cardiomyopathy, the most common cause of heart failure. The research demonstrates a pathogenic role for CELF1 in contributing to the Cx43 mRNA degradation during heart failure and was published in Circulation Research. The first author Kuei-Ting Chang is a Ph.D. student in the Program in Molecular Medicine at National Yang-Ming University and Academia Sinica.
Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy. One of the causes of mortality in DCM patients is arrhythmia-related death. Under pathological conditions, a distinctive feature of electrical changes is a change in electrical coupling due to abnormal expression of connexin 43 (Cx43), the most abundant cardiac gap junction protein. In the adaptive or compensatory cardiac hypertrophic stage, Cx43 expression is increased and often associated with lateralization, whereas in dilated cardiomyopathy or in the decompensatory stage, Cx43 expression is decreased and associated with heterologous distribution in the ventricle. The regulatory mechanism controls the transition from compensated condition to decompensation and heart failure leading to reduced Cx43 expression is largely unknown.
CELF1 (CUGBP, Elav-like family member 1) is an RNA binding protein whose increased expression has been implicated in the cardiac pathogenesis of myotonic dystrophy type 1 (DM1), a CTG repeat expansion disorder. In the DM1 heart specific mouse model, expression of expanded CUG RNA in cardiomyocytes induces PKC-mediated CELF1 hyperphosphorylation and stabilization recapitulating the clinical features including arrhythmia, contractility dysfunction and DCM. However, how elevated CELF1 level leads to cardiac dysfunction, such as conduction defect, DCM and heart failure, remains unclear. Given that CELF1 expression is not changed in a model for compensated hypertrophy in pressure overload condition, whether elevated CELF1 level is a unique feature of the DM1 heart or a shared feature of other cardiovascular diseases has not been determined.
In this study, we showed that CELF1 mediated Cx43 mRNA degradation by binding to Cx43 and interacting with an exoribonuclease RRP6 in an RNA-independent and nucleus specific manner. Increased CELF1 expression accompanied with RRP6 upregulation and downregulation of CELF1 mediated target genes including Cx43 was detected in 3 mouse models of DCM: DM1, CELF1 overexpression and myocardial infarction (MI). Importantly, using a heart-specific Celf1 knockout mouse model we showed that Celf1 depletion in infarcted heart ameliorated the contractility dysfunction and preserved Cx43 mRNA level. The results not only demonstrate a pathogenic role for CELF1 in contributing to the Cx43 mRNA degradation during heart failure, also suggest increased CELF1 expression may be a common feature of DCM and CELF1 might be a potential therapeutic target in both acute and chronic heart failure.
The complete list of authors is: Kuei-Ting Chang, Ching-Feng Cheng, Pei-Chih King, Shin-Yi Liu, and Guey-Shin Wang.
Dr. Guey-Shin Wang, Institute of Biomedical Sciences, Academia Sinica
Email: firstname.lastname@example.org; (Tel) +886-2-2652-3051