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. 2010 Nov 22;120(12):4375–4387. doi: 10.1172/JCI37649

Figure 8. S107 but not metoprolol or carvedilol improves cardiac function in RyR-S2808D+/+ mice after MI.

Figure 8

(A and B) Echocardiographic measurements at baseline, 1, 3, and 5 weeks after MI. Treatment started 1 week after MI (arrows). (A) In the WT group, S107, metoprolol (Met), and carvedilol (Carv) showed a beneficial effect at the end of study (week 4 of treatment). (B) In the RyR2-S2808D+/+ group, only S107 inhibited HF progression. *P < 0.05 versus vehicle group. (C and D) Hemodynamic data were obtained by cardiac catheterization at the end of study. (C) In the WT group, S107, metoprolol, and carvedilol improved LV systolic function (dP/dtmax). (D) In the RyR2-S2808D+/+ group, only S107 improved LV systolic function. The number of mice in each treatment group is indicated by the parenthetical numbers over each bar. Black represents vehicle; light blue represents low-dose metoprolol (30 mg/kg/d); dark blue represents high-dose metoprolol (300 mg/kg/d); green represents carvedilol (10 mg/kg/d); and red represents S107 (30 mg/kg/d). *P < 0.05 versus vehicle group. (E) Representative immunoblots from in vivo studies. Equivalent amounts of RyR2 were immunoprecipitated from cardiac lysates using an anti-RyR2 antibody. In the WT group, MI increased RyR2-S2808 PKA phosphorylation and calstabin2 depletion from the RyR2 channel complex and metoprolol decreased RyR2-S2808 PKA phosphorylation and reduced depletion of calstabin2 from the cardiac RyR2 channel complex. In the RyR2-S2808D+/+ group, calstabin2 was depleted from RyR2 channel complex in both vehicle- and metoprolol-treated groups, whereas S107 reduced depletion of calstabin2 from the cardiac RyR2 channel complex. (F) Pooled data from 3 separate immunoblots. *P < 0.05 versus sham; #P < 0.05 versus metoprolol treated.