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Protein Disulfide Isomerase Involvement in Dilated Cardiomyopathy Caused by Filamin C Deficiency in Male Mice
He Xuan1, Chenghao Fan1, Xue Bai1
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Loss-of-function variants in the FLNC gene, which encodes Filamin C, cause dilated cardiomyopathy with a high risk of life-threatening arrhythmias. Therapies targeting the underlying mechanism of FLNC-related dilated cardiomyopathy remain limited. In this study, we observed that deletion of Flnc in cardiomyocytes of mice led to prominent ventricular dilation, cardiac dysfunction, and cardiac fibrosis. This phenotype closely resembles FLNC-related dilated cardiomyopathy in humans. RNA sequencing analysis revealed activation of protein disulfide isomerase (PDI) in Flnc-deleted cardiac tissues, as confirmed by immunoblotting. Treatment with the specific PDI inhibitor E64FC26 improved cardiac function, reduced cardiac fibrosis, and decreased cardiomyocyte apoptosis in cardiomyocyte-specific Flnc-deleted mice. We provide evidence that PDI is involved in the cardiac remodeling induced by Filamin C deficiency, and that treatment with the PDI inhibitor resulted in beneficial effects in mice with dilated cardiomyopathy caused by Flnc deletion. Our findings suggest that PDI could be a promising therapeutic target for FLNC-related dilated cardiomyopathy.
Insights
Loss-of-function variants in the FLNC gene cause dilated cardiomyopathy. Targeting protein disulfide isomerase (PDI) with a PDI inhibitor improved cardiac function and reduced fibrosis in a mouse model of FLNC-related heart disease.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Loss-of-function variants in the FLNC gene, encoding Filamin C, are linked to dilated cardiomyopathy and life-threatening arrhythmias.
- Current therapies for FLNC-related dilated cardiomyopathy are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of protein disulfide isomerase (PDI) in cardiac remodeling associated with Filamin C deficiency.
- To evaluate the therapeutic potential of a PDI inhibitor in a mouse model of FLNC-related dilated cardiomyopathy.
Main Methods:
- Generation of cardiomyocyte-specific Flnc-deleted mice to mimic human FLNC-related dilated cardiomyopathy.
- RNA sequencing and immunoblotting to identify molecular changes in Flnc-deleted cardiac tissue.
- Assessment of cardiac function, fibrosis, and apoptosis following treatment with a PDI inhibitor (E64FC26).
Main Results:
- Flnc deletion in mice resulted in ventricular dilation, cardiac dysfunction, and fibrosis, mirroring human FLNC-related dilated cardiomyopathy.
- RNA sequencing revealed activation of protein disulfide isomerase (PDI) in Flnc-deficient hearts.
- PDI inhibitor treatment improved cardiac function, reduced fibrosis, and decreased cardiomyocyte apoptosis in the mouse model.
Conclusions:
- Protein disulfide isomerase (PDI) is implicated in cardiac remodeling due to Filamin C deficiency.
- Targeting PDI with inhibitors demonstrates therapeutic benefits in a preclinical model of FLNC-related dilated cardiomyopathy.
- PDI inhibition represents a potential therapeutic strategy for FLNC-related dilated cardiomyopathy.
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