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

Figures

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  FIGURE 1. Flnc iKO mice presented the malignant dilated cardiomyopathy phenotype. (A) Schematic of Flnc iKO mouse generation. (B) Western blot and quantification of Filamin C levels in Flnc iKO mice hearts 7 days after tamoxifen treatment (20 mg/kg/d for 5 days). Flnc fl/fl mouse hearts served as controls (n = 3, each). (C) Haematoxylin & Eosin‐stained heart sections from Flnc iKO mice and control Flnc fl/fl mice. Scale bar, 2000 μm. (D) Heart weight/body weight ratios (HW/BW) of Flnc iKO mice and Flnc fl/fl mice 2 weeks after tamoxifen treatment (n = 5, each). (E) Images and quantification of cardiac fibrosis in Sirius Red‐stained sections from Flnc iKO mice and Flnc fl/fl controls (n = 3, each). Scale bar, 50 μm. (F–H) Representative echocardiography images and quantification of parameters, including ejection fraction, fractional shortening, left ventricular end‐diastolic anterior wall thickness (LVAWd) and the left ventricular end‐diastolic posterior wall thickness (LVPWd) of Flnc iKO mice (n = 4) and control Flnc fl/fl mice (n = 6) 2 weeks after tamoxifen treatment. (I, J) Representative images of echocardiography and quantification analysis of E/e' ratio of Flnc iKO mice and control…

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  FIGURE 2. Inhibiting PDI with E64FC26 protected cardiac function and reduced cardiomyocyte apoptosis in Flnc iKO mice. (A) Schematic of experimental design. For Flnc iKO mice, E64FC26 (2 mg/kg) or vehicle DMSO was administered by intraperitoneal injection 3 times per week for 2 weeks. Hearts were harvested immediately after drug administration for PDI expression assay. Two weeks after administration completion, cardiac function, cardiac fibrosis and apoptosis were evaluated. (B) Western blot analysis and quantification of PDI, IRE1α, and phosphorylation of IRE1α levels in Flnc iKO mice, after E64FC26 or DMSO treatment (n = 3, each). (C) RT‐qPCR analysis of Nppa and Nppb expression in hearts of Flnc iKO mice treated with E64FC26 or DMSO (n = 6, each). (D) Representative echocardiography M‐mode images of Flnc iKO mice treated with E64FC26 or DMSO after 2 weeks of drug administration completion. (E, F) Echocardiographic measurements of ejection fraction, fractional shortening, left ventricular end‐diastolic anterior wall thickness (LVAWd) and the left ventricular end‐diastolic posterior wall thickness (LVPWd) of Flnc iKO mice treated with E64FC26 (n = 9) or DMSO (n = 11) after 2 weeks of drug…