Lillo MA , Himelman E , Shirokova N , Xie LH , Fraidenraich D , Contreras JE .

R01 GM099490 NIGMS NIH HHS , R01 HL093342 NHLBI NIH HHS , R01 HL133294 NHLBI NIH HHS , R01 HL141170 NHLBI NIH HHS

             membrane depolarization

	Figure 1 Isoproterenol induces triggered activity in Dmdmdx cardiomyocytes via opening of Cx43 hemichannels. (A) Representative action potential (AP) traces of WT, Dmdmdx, and Dmdmdx Cx43+/– isolated cardiomyocytes. Cells were stimulated with 1 μM isoproterenol (Iso, shown in green) in the absence or presence of Cx43 or Cx45 hemichannel blockers contained inside the pipette: Gap19 (232 ng/μL), Cx43 CT antibody (abCx43; 2.5 ng/μL), or Cx45 CT antibody (2.5 ng/μL). Arrow indicates electrical stimulation pulse. (B) Quantification of triggered activity (TA) induced by Iso observed in A. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (C) Resting membrane potential of WT and Dmdmdx cardiomyocytes. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (D) Assessment of Cx43 hemichannel activity in the whole heart via ethidium uptake. Isolated hearts were perfused with buffer containing 5 μM ethidium after vehicle or Iso (5 mg/kg IP). The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. *P < 0.05 vs. vehicle WT; †P < 0.05 vs. vehicle Dmdmdx.
	Figure 2 Biotin perfused in intact hearts interacts only with plasma membrane of cardiomyocytes at the lateral side. (A) Representative immunofluorescence against N-cadherin (green) and biotin (red) in a Dmdmdx heart sample. Biotin was perfused for 60 minutes before heart fixation. Cryosections were stained with wheat germ agglutinin (WGA, blue). Note that biotin was positively stained only at the lateral borders of cardiomyocytes and not at intercalated discs. (B) Western blot analysis and quantification of Cx43 from biotin-perfused hearts (biotinylation). Bottom row represents Cx43-immunoblotted samples from heart lysates prior to pulldown (total Cx43). Biotinylated Cx43 levels were expressed as fold change relative to total Cx43 protein levels per sample. Note that biotin did not interact with intracellular proteins (eNOS) and intercalated disc proteins (N-cadherin). The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. *P < 0.05 vs. WT control; †P < 0.05 vs. Dmdmdx control.
	Figure 3 Iso increases S-nitrosylated levels of Cx43 at the lateral side of Dmdmdx cardiomyocytes. (A) Top and middle gels were loaded with S-nitrosylated proteins pulled down from heart samples using the biotin switch assay. Top gel was, then, blotted against Cx43, and the middle gel is the corresponding Ponceau staining. Lower blot was loaded using total cardiac proteins and blotted against Cx43. The bottom graph is the quantification for 5 independent blots using the ratio for S-nitrosylated Cx43/Ponceau. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. *P < 0.05 vs. WT control, and †P < 0.05 vs. WT Iso. (B) Analysis performed by PLA of the interaction between Cx43 and S-nitrosylation. Plasma membrane stained with wheat germ agglutinin (WGA) and S-nitrosylated Cx43 (Cx43-SNO) are shown in green and red, respectively. Representative images of n = 5 per group. (C) Assessment of Cx43 hemichannel activity in isolated Dmdmdx hearts perfused with buffer containing 5 μM ethidium bromide after or without treatment with Iso. Arrows show nuclei. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA test plus Tukey’s post hoc test. *P < 0.05 vs. vehicle WT; †P < 0.05 vs. vehicle Dmdmdx. (D) Top and middle gels were loaded with S-nitrosylated proteins pulled down from human heart samples using the biotin switch assay. Top gel was, then, blot against Cx43 and the middle gel is the corresponding ponceau staining. Lower blot was load using total cardiac proteins and blot against Cx43. (E) Analysis performed by PLA of the interaction between Cx43 and S-nitrosylation in human samples. Note that Cx43 is S-nitrosylated at the lateral side of DMD human samples compare to non-DMD.
	Figure 4 Blockade of NO production prevents Cx43 hemichannel–mediated TA and arrhythmias in Dmdmdx mice. (A) Representative action potential traces of WT and Dmdmdx isolated cardiomyocytes. Cells were stimulated with 1 μM Iso in the presence of 100 μM l-NAME. Arrow indicates electrical stimulation. (B) Quantification of TA induced by Iso observed in A. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (C) Resting membrane potential of WT and Dmdmdx cardiomyocytes. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. (D) Representative ECG traces of 5- to 6-month-old WT and Dmdmdx mice that were previously treated or not with 2 mM l-NAME (an unspecific NOS blocker) via drinking water. ECG baseline and ECG after Iso treatment (5 mg/kg IP) are shown for comparison. (E) Arrhythmia score based on predetermined scale: 0, no arrhythmias; 1, single premature ventricular contractions (PVCs); 2, double PVCs; 3, triple PVCs or nonsustained ventricular tachycardia (VT); 4, sustained VT or atrioventricular (AV) block; and 5, death. *P < 0.0001 versus WT; †P < 0.0001 versus Dmdmdx l-NAME. The number in parentheses indicates the n value. Statistical significance determined by 1-way ANOVA plus Tukey’s post hoc test.
	Figure 5 Exogenous NO-induced TA in Dmdmdx cardiomyocytes. (A) Representative AP traces of WT, Dmdmdx, and DmdmdxCx43+/– isolated cardiomyocytes. Cells were stimulated with 1 μM DEENO in the absence or presence of Cx43 hemichannel blockers, Gap19 (232 ng/μL) and Cx43 CT antibody (abCx43; 2.5 ng/μL). Arrow indicates electrical stimulation pulse. (B) Quantification of TA induced by DEENO in A. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (C) Resting membrane potential of WT and Dmdmdx cardiomyocytes upon DEENO stimulation. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05.
	Figure 6 NO-activated currents from oocytes expressing Cx43 hemichannels. (A) Representative current traces before and after application of 10 μM DEENO in a noninjected oocyte or an oocyte expressing Cx43. Oocytes were clamped to −80 mV, and square pulses from −80 mV to +90 mV (in 10-mV steps) were then applied for 2 seconds. At the end of each pulse, the membrane potential was returned to −80 mV. Normalized currents were obtained from the ratio between recorded current after and before DEENO treatment. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05 vs. noninjected. (B) Intracellular injection of Gap19 (232 ng/μL) or a Cx43 CT antibody (2.5 ng/μL) reduced NO-induced Cx43 hemichannel currents. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. *P < 0.05 vs. Cx43 with Gap19; †P < 0.05 vs. Cx43 with AbCx43. (C) Changes in resting membrane potential in the presence or absence of 10 μM DEENO. Cx43 hemichannel blockers restored normal resting membrane potential. Comparisons between groups were made using 1-way ANOVA; *P < 0.05. (D) Extracellular calcium dependence of the resting membrane potential evoked by 10 μM DEENO in oocytes expressing Cx43 hemichannels. The number in parentheses indicates the n value. Comparisons between groups were made using 2-tailed Student’s t test; *P < 0.05 vs. control.
	Figure 7 Position C271, but not C260 and C298, was S-nitrosylated and mediated NO-induced hemichannel currents. (A) Representative current traces for oocytes expressing Cx43 with a deleted CT and Cx43 mutants C260S, C271S, and C298S. Black and red traces correspond to voltage step–evoked currents in the absence or presence of 10 μM DEENO, respectively. Oocytes were clamped to −80 mV, and square pulses from −80 mV to +90 mV (in 10-mV steps) were then applied for 2 seconds. At the end of each pulse, the membrane potential was returned to −80 mV. Graph shows normalized fold increase of DEENO current after treatment at different voltages. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05 vs. Cx43ΔCT; †P < 0.05 vs. Cx43C271. (B) DEENO decreased the resting membrane potential in oocytes expressing Cx43 mutants C260S and C298S but not in those expressing the Cx43ΔCT or Cx43 mutant C271S. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA test; *P < 0.05 vs. control. (C) Top gel was loaded with S-nitrosylated proteins pulled down using the biotin switch assay and blotted against Cx43. Bottom Western blot was loaded with total proteins of oocytes expressing Cx43 against Cx43. The number in parentheses indicates the n value. Comparisons between groups were made using Student’s t test; *P < 0.05 vs. control.
	Fig S1. Injection of hyperpolarizing and depolarizing current are sufficient to regulated TA in isolated Dmdmdx cardiomyocytes. A) Representative action potentials traces of Dmdmdx isolated cardiomyocytes in the absence or presence of 1μM isoproterenol (Iso). Hyperpolarizing (20-12 pA) or depolarizing currents (12-8 pA) were injected to maintain the resting membrane potential close to -70 mV (value observed in WT cardiomyocytes) or near - 60 mV (value observed in Dmdmdx cardiomyocytes treated with Iso), respectively. Arrow indicates electrical stimulation pulse. B) Quantification of TA observed in conditions shown in (A). The number in parentheses indicates the n value. Comparisons between groups were made using two-way ANOVA plus Tukey post-hoc test, *P<0.05.
	Fig S2. Na+/Ca2+ exchanger (NCX) inhibition does not prevent Iso-induced triggered activity in Dmdmdx cardiomyocytes. (A) Representative action potential traces of Dmdmdx isolated cardiomyocytes. Cells were stimulated with 1µM isoproterenol (Iso) in the presence of 10 µM SEA0400 a selective inhibitor of NCX. Arrow indicates electrical stimulation pulse. B) Quantification of TA observed in conditions shown in (A). The number in parentheses indicates the n value. Comparisons between groups were made using Student´s t-test, *P<0.05 vs Vehicle. C) Resting membrane potential of Dmdmdx cardiomyocytes. The number in parentheses indicates the n value. Comparisons between groups were made using Student´s t-test, *P<0.05 vs vehicle
	Fig S3. WT and in Dmdmdx 992 hearts do not show PI uptake after mice were treated with Iso. Representative images of isolated hearts perfused with Tyrode buffer containing 50 μM PI after treatment with Iso (5mg/kg, IP). Cryosections were stained with wheat germ agglutinin (WGA, green) and nuclei were stained blue with DAPI mounting reagent. Representative images of n = 3 per group.
	Fig S4. DmdmdxCx43+/- cardiomyocytes display a lower level of laterally localized Cx43 thanDmdmdx. A) Western blot analysis (top) and quantification (graph) of Cx43 from biotin perfused hearts (biotinylation). Bottom row represents Cx43-immunoblotted samples from heart lysates prior to pulldown (total Cx43). Biotinylated Cx43 levels were expressed as fold change relative to total Cx43 protein levels per sample. The number in parentheses indicates the n value. Comparisons between groups were made using two-way ANOVA plus Tukey post-hoc test. *P<0.05 vs Control Dmdmdx: Cx43(+/-), †<0.05 vs Dmdmdx.
	Fig S5. Dystrophic hearts with lower levels of Cx43 prevent the Iso-induced S-nitrosylated levels of Cx43. A) Top: Western blot detection of Cx43 and Middle: Ponceau staining of samples subjected to the biotin switch assay. Lower: Western blot detection of Cx43 in total cardiac protein lysates. Graph: quantification of 6 independent blots using the ratio of SNO-Cx43/Total. Comparisons between groups were made using two-way ANOVA plus Tukey post-hoc test. *P<0.05 vs WT control,†<0.05 vs WT Iso, **<0.05 vs Dmdmdx. B) Proximity Ligation assay (PLA) of Cx43 and Snitrosylation in heart sections of WT, Dmdmdx and Dmdmdx: Cx43 1015 (+/-) mutants. Detection of Wheat germ agglutinin (WGA) (green) and S-nitrosylated Cx43 (Cx43-SNO) (red), respectively. Representative images of n = 4 per group.
	Fig S6. Cx43 variants carrying a carboxyterminal truncation or a C271S mutation do not affect gating when co-expressed as heteromeric channel with Cx26S17F. (A) Representative current traces elicited by a voltage pulse from -80 to 0 mV from oocytes expressing heteromeric channels formed by full length, CT truncated Cx43 or Cx43C271S with Cx26S17F. Black and red traces correspond to voltage activated hemichannel currents in the absence or presence of 10 μM DEENO, respectively. Representative traces of n = 9 per group. (B) Nitric oxide did not activate homomeric Cx26 and Cx26S17F hemichannels. Representative current traces elicited by a voltage pulse from -80 to 0 mV for an oocyte expressing Cx26 and Cx26S17F. Black and red traces correspond to voltage activated hemichannel currents in the absence or presence of 10 μM DEENO, respectively. Representative traces of n = 6 per group.
	Fig. S7. WT, Dmdmdx cardiomyocytes display similar K+ currents. A) Representative current traces before and after application of 100 μM Gap19 and/or 1μM Iso in WT and Dmdmdx isolated cardiac cells. K+ currents were measured using the orange section detected during a ramp protocol. A negative ramp (from +40 to -120 mV) was used to prevent activating the voltage-gated sodium channel. B) Quantification of reversal membrane potential detected in conditions shown in (A). The number in parentheses indicates the n value.
	Fig S8. Cx43 hemichannels are involved in the prolongation of APD in WT and dystrophic cardiomyocytes upon isoproterenol treatment. A) Representative action potential traces of WT, Dmdmdx and DmdmdxCx43+/- isolated cardiomyocytes. Cells were stimulated with 1µM isoproterenol (Iso) in the absence or presence of Cx43 blockers contained inside the pipette: Gap19 (232ng/µL) and Cx43 CT antibody (abCx43; 2.5ng/µL). Arrows represent electrical stimulation. Note that Dmdmdx isolated cardiomyocytes have extended APD compared to WT and DmdmdxCx43+/- isolated cardiac cells. B) Quantification of APD observed in (A). The number in parentheses indicates the n value. Comparisons between groups were made using two-way ANOVA test plus Tukey post-hoc test. *P<0.05, † <0.05 vs WT isoproterenol.
	Fig S9. Nitric oxide canonical pathway (cGMP-PKG) does not mediate TA in isolated cardiomyocytes and Cx43 hemichannels activation. A) Representative action potentials traces from Dmdmdx 1051 isolated cardiomyocytes. Cells were stimulated with 1μM Iso in the absence or presence of ODQ (a highly selective, irreversible, inhibitor of soluble guanylyl cyclase) or KT 5823 (selective protein kinase G inhibitor) contained inside the pipette: ODQ (3 µM) and KT 5823 (1 µM). Arrow indicates electrical stimulation pulse. Note that both inhibitors ODQ and KT 5823 did not affect the TA and the Vm induced by Iso stimulation. The number in parentheses indicates the n value. Comparisons between groups were made using two-way ANOVA plus Tukey post-hoc test *P<0.05 vs WT. B) Representative current traces after application of 10 μM DEENO in an oocyte expressing Cx43 in the absence or presence of intracellular injections of ODQ (3 µM final intracellular concentration) and KT 5823 (1 µM final intracellular concentration). Oocytes were clamped to −80 mV, and square pulses from −80 mV to +90 mV (in 10 mV steps) were then applied for 2s. Normalized currents were obtained from the ratio between recorded current after and before DEENO treatment. Note that soluble guanylyl cyclase and protein kinase G inhibition did not significantly affect NO-induced hemichannel currents in oocytes expressing Cx43.

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