Dapagliflozin protects against dilated cardiomyopathy progression by targeting NLRP3 inflammasome activation

Figures

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  Fig. 1. Dapagliflozin treatment significantly improved cardiac functions in doxorubicin-induced DCM mice. A Murine cardiac functions are analyzed by echocardiography. B The left ventricular ejection fraction (LVEF), the left ventricular fractional shortening (LVFS), the left ventricular internal dimensions (LVIDd), and the left ventricular internal dimensions (LVIDs) were measured at the end of the experiment (n = 10 per group). C Representative images of the staining of HE in heart sections from mice treated with doxorubicin or dapagliflozin (scale bars, 2 mm)

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  Fig. 2. Dapagliflozin inhibited the activation of the NLRP3 inflammasome in doxorubicin-induced DCM mice. A Relative NLRP3, ASC, Caspase-1, and AIM2 mRNA expression level were detected by real-time PCR in control, Dox, and Dox + Dapa mice. (n = 5 per group). B Representative immunofluorescence images of NLRP3 in control, Dox, and Dox + Dapa mice. cTNT (red), NLRP3 (green), and DAPI (blue) (scale bars, 100 μm). C–D Representative western blot of NLRP3 inflammasome pathway and densitometric analysis in control, Dox, and Dox + Dapa mice (n = 5).​ *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

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  Fig. 3. Dapagliflozin inhibited the expression of the inflammatory factors interleukin (IL)-6, L-1β, and IL-18 in cardiac tissues. A Representative immunohistochemical images of IL-6, IL-1β, and IL-18 and densitometric analysis in control, Dox, and Dox + Dapa mice (scale bars, 50 μm). B Representative western blot of IL-6, pro-IL-1β, cleaved-IL-1β, IL-18, and densitometric analysis in control, Dox, and Dox + Dapa mice (n = 5). **P < 0.01, ***P < 0.001, ****P < 0.0001

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  Fig. 4. In vitro, dapagliflozin suppressed the Dox-induced inflammatory response. A Representative immunofluorescence images of NLRP3 inflammasome in control, Dox, and Dox + Dapa cells (scale bars, 100 μm). B Representative western blot of NLRP3 inflammasome pathway and densitometric analysis in control, Dox, and Dox + Dapa cells.​ C Representative western blots of inflammatory factors IL-6, pro-IL-1β, cleaved-IL-1β, IL-18, and densitometric analysis in control, Dox, and Dox + Dapa cells. D ELISA analysis of inflammatory factors (IL-6, IL-1β, and TNF-α) in cell supernatant of control, Dox, and Dox + Dapa cells. (n = 5 per group). ***P < 0.001, ****P < 0.0001

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  Fig. 5. Dapagliflozin reduced the expression of NLRP3 inflammasome through the inhibition of TLR4 by p38. A–B Representative western blots (A) and densitometric analysis (B)of TLR4, P-p38, and P-ERK in control, Dox, Dox + Dapa, and Dox + SB cells. ***P < 0.001, ****P < 0.0001