Extended Data Fig. 8: LCL161 treatment reduces MI injury.

a) in vivo dose titration of LCL161. Peripheral blood cells were isolated 48 h following stimulation of mice with isoproterenol (10 mg/kg) and gavage of vehicle control or 2, 10 or 25 mg/kg of LCL161. Data shown is of representative 2 vehicle control-gavaged mice (top) or 10 mg/kg-gavaged LCL161 (bottom). b) Expression of inflammatory signal transduction intermediates by ex vivo-differentiated bone marrow-derived dendritic cells. Cell lysates were collected following 48-hour stimulation as indicated in presence or absence of LCL161. Immunoblot is representative of 2 similar experiments. c) flow cytometry gating for cell quantitation of monocytes or neutrophils from hearts of MI-treated C57Bl/6 mice receiving either vehicle (top) or LCL161 (10 mg/kg; bottom). Dotplot is representative of 5 mice per treatment. d) intracellular flow cytometry measuring cardiac Th17 cells from mice treated as in c). Controls: N = 2; MI-operated: N = 3 per group. e) LCL161-treated cIAP1^−/−, but not cIAP2^−/−, mice demonstrate improvement in ejection fraction, remodeling and heart weight improvement following MI. WT: MI + Vehicle: N = 5, MI + LCL: N = 5; cIAP1^−/−: MI + Vehicle: N = 6, MI + LCL: N = 6; cIAP2^−/−: MI + Vehicle: N = 8, MI + LCL: N = 7. Data are presented as aggregates from two representative experiments. f) reduced inflammatory cell infiltrate in hearts of cIAP1^−/− mice treated with LCL161. Controls: N = 2; MI-operated: N = 4 vehicle treated; N = 5 LCL treated. g) Quantitative PCR of heart tissue isolates at 28 days post-MI for measurement of injury/inflammation gene transcription. N = 4/group for each target gene. h) Quantitation of spleen and bone marrow myeloid (CD11b⁺) cells Day 28 post-MI. Controls: N = 2/mouse strain; MI: N = 4/mouse strain. Error bars denote Mean +/- SD; p values were calculated using one-way ANOVA with Bonferroni’s correction (d, f) two-way ANOVA with Bonferroni’s correction (e) or two-sided t test (g).

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