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. 2022 Jul 4;30(11):3477–3498. doi: 10.1016/j.ymthe.2022.06.016

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Vcp attenuates mPTP opening by reducing Vdac1 expression

(A) Changes in the expression level of the Vdac1 protein after Vcp overexpression; ∗p < 0.05, n = 6. Mitochondria were extracted from P1 CMs, and western blotting was then performed to detect the Vdac1 protein. (B) Changes in the expression level of the Vdac1 protein after 5 μΜ ML240 treatment; ∗p < 0.05, n = 6. (C) Changes in the expression level of the Vdac1 protein after circSamd4 overexpression and/or 5 μΜ ML-240 treatment; ∗p < 0.05, n = 6. (D) Detection of the MMP in P1 CMs treated with VBIT-12 using the flow cytometry assay. P1 CMs were incubated with VBIT-12 (20 μM) for 24 h and then incubated with H₂O₂ (20 μM) for 8 h. JC-1 monomer, green; J-aggregate, red. ∗p < 0.05, n = 6. (E) Detection of the MMP in P1 CMs treated with VBIT-12 using an immunofluorescence assay. (F) Detection of mitochondrial ROS in CMs treated with VBIT-12. ∗p < 0.05, n = 6. (G) Detection of DDR activation in CMs treated with VBIT-12. ∗p < 0.05, n = 6. (H) Detection of Ki67+ CMs after VBIT-12 treatment. Ki67+ CMs are indicated by arrows, ∗p < 0.05, n = 6. (I) Detection of pH3+ CMs after VBIT-12 treatment. ∗p < 0.05, n = 6. (J) Detection of the MMP in P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment using the flow cytometry assay. The CMs were treated with 20 μΜ H₂O₂ prior to detection. ∗p < 0.05, n = 6. (K) Detection of the MMP in P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment using the immunofluorescence assay. JC-1 monomer, green; J-aggregate, red. (L) Detection of mitochondrial ROS after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (M) Detection of DDR activation after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (N) Detection of pH3+ P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (O) Schematic illustrating the main finding of this study: Nrf2-upregulated circSamd4 binds to the Vcp protein and promotes Vcp mitochondrial translocation, thereby reducing Vdac1 expression and attenuating mPTP opening. CircSamd4 overexpression decreases oxidative stress production and triggers CM proliferation, leading to cardiac repair after MI.

Vcp attenuates mPTP opening by reducing Vdac1 expression

(A) Changes in the expression level of the Vdac1 protein after Vcp overexpression; ∗p < 0.05, n = 6. Mitochondria were extracted from P1 CMs, and western blotting was then performed to detect the Vdac1 protein. (B) Changes in the expression level of the Vdac1 protein after 5 μΜ ML240 treatment; ∗p < 0.05, n = 6. (C) Changes in the expression level of the Vdac1 protein after circSamd4 overexpression and/or 5 μΜ ML-240 treatment; ∗p < 0.05, n = 6. (D) Detection of the MMP in P1 CMs treated with VBIT-12 using the flow cytometry assay. P1 CMs were incubated with VBIT-12 (20 μM) for 24 h and then incubated with H₂O₂ (20 μM) for 8 h. JC-1 monomer, green; J-aggregate, red. ∗p < 0.05, n = 6. (E) Detection of the MMP in P1 CMs treated with VBIT-12 using an immunofluorescence assay. (F) Detection of mitochondrial ROS in CMs treated with VBIT-12. ∗p < 0.05, n = 6. (G) Detection of DDR activation in CMs treated with VBIT-12. ∗p < 0.05, n = 6. (H) Detection of Ki67+ CMs after VBIT-12 treatment. Ki67+ CMs are indicated by arrows, ∗p < 0.05, n = 6. (I) Detection of pH3+ CMs after VBIT-12 treatment. ∗p < 0.05, n = 6. (J) Detection of the MMP in P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment using the flow cytometry assay. The CMs were treated with 20 μΜ H₂O₂ prior to detection. ∗p < 0.05, n = 6. (K) Detection of the MMP in P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment using the immunofluorescence assay. JC-1 monomer, green; J-aggregate, red. (L) Detection of mitochondrial ROS after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (M) Detection of DDR activation after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (N) Detection of pH3+ P1 CMs after circSamd4 overexpression, 5 μΜ ML-240 and/or 20 μΜ VBIT-12 treatment. ∗p < 0.05, n = 6. (O) Schematic illustrating the main finding of this study: Nrf2-upregulated circSamd4 binds to the Vcp protein and promotes Vcp mitochondrial translocation, thereby reducing Vdac1 expression and attenuating mPTP opening. CircSamd4 overexpression decreases oxidative stress production and triggers CM proliferation, leading to cardiac repair after MI.