Protein Disulfide Isomerase Involvement in Dilated Cardiomyopathy Caused by Filamin C Deficiency in Male Mice.

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.