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. 2020 Apr 28;141(17):1427-1429.
doi: 10.1161/CIRCULATIONAHA.119.041664. Epub 2020 Apr 27.

Kruppel-Like Factor 15 Regulates the Circadian Susceptibility to Ischemia Reperfusion Injury in the Heart

Le Li  1   2 , Hui Li  1 , Chih-Liang Tien  1 , Mukesh K Jain  3   4 , Lilei Zhang  1
Affiliations

Kruppel-Like Factor 15 Regulates the Circadian Susceptibility to Ischemia Reperfusion Injury in the Heart

Le Li et al. Circulation. .
No abstract available

Keywords: NAD; circadian rhythm; ischemia-reperfusion injury; myocardial infarction.

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Figures

Figure.
Figure.
KLF15 regulates circadian I/R susceptibility of the heart. A, Mouse cardiac KLF15 expression during a 24-hour day by immunoblot. ZT, zeitgeber time. ZT 22 was set to 1 (n = 3 per time point, *: p< 0.05, **: p< 0.01, ***: p<0.001 vs. ZT22, one-way ANOVA with Bonferroni correction). Shading indicates the light and dark periods under 12:12 light-dark conditions. B, qRT-PCR of Klf15 in human heart samples from patients with ischemic cardiomyopathy (ICM) and controls. (*: p< 0.05, 2-sided Student’s t-test). C, Top, Experiment design. Bottom left, Representative TTC staining. Bottom right, Percent of infarct over area at risk. (n=8–13, *: p<0.05 vs. controls at ZT2; #: p<0.05 vs. controls at ZT 14, two-way ANOVA with Bonferroni correction correction). D, all samples are collected at ZT14 except top left panel. Top left, MnSOD activity in cKLF15 KO mice and control mice hearts. (n=6–7, *: p<0.005 vs. control at ZT2, **: p<0.0001 vs. control at ZT2, #: p<0.005 vs control at ZT14, two-way ANOVA with Bonferroni correction). Top right, MnSOD and MnSODK122 acetylation level measured by immunoblot. (n=4, *: p<0.001, 2-tailed Student’s t test, Holm-Sidak correction). Middle left, Cardiac mitochondrial total protein acetylation of cKLF15 KO mice and littermate control mice. (n=3–4). Middle right, SIRT3 protein level determined by immunoblot blot. Bottom, Cardiac total NAD, NAD+ level and NAD+/NADH ratio from cKLF15 KO and littermate control mice. (n=6–7, *: p<0.05 vs. litter mate controls, 2-tailed Student’s t test, Holm-Sidak correction). E, Top, Experiment design. Middle left, Representative TTC staining. Middle right, Percent of infarct over area at risk. (n=6, *: p<0.01vs. littermate controls without NMN, #: p<0.05 vs. cKLF15 KO mice without NMN, two-way ANOVA with Bonferroni correction). Bottom, cardiac total NAD, NAD+ level and NAD+/NADH ratio from cKlf15 KO and littermate control mice pretreated with NMN/PBS prior to I/R injury at ZT14 (n=4, *; p<0.05 vs. litter mate control without NMN, #: p<0.01 vs. cKlf15 KO mice without NMN; 2-tailed Student’s t-test, Holm-Sidak correction). F, Top, Total NAD pool, NAD+, and the NAD+/NADH ratio in cKLF15 KO mice and littermate control hearts. (n = 3–4 per time point, *: p<0.05, **: p<0.01, ***: p<0.001, 2-tailed Student’s t test, Holm-Sidak correction). Middle left, Experiment design and representative TTC staining. Middle right, Percent of infarct over area at risk (bottom right). (n=6–7, *: p<0.01vs. mice without NMN, 2-tailed Student’s t test, Holm-Sidak correction). Bottom, cardiac total NAD, NAD+ level and NAD+/NADH ratio from control mice pretreated with NMN/PBS prior to I/R injury at ZT2 (n=3, *: p<0.05 vs. mice without NMN, 2-tailed Student’s t-test, Holm-Sidak correction). G, Top, cardiac Nampt RNA level in cKlf15 KO mice and littermate controls in 24hrs. (n = 3–6; *: p<0.05, two-way ANOVA with Bonferroni correction). Bottom, cardiac NAMPT protein level determined by immunoblot blot. (n=4, **: p<0.01, ***: p<0.001, ****: p<0.0001, two-way ANOVA with Bonferroni correction). H, Luciferase reporter assays in 3T3 cells. Genomic locus of mouse Nampt promoter region was shown adapted from the UCSC genome browser. ENCODE data for H3K27ac in 8 weeks mouse heart is shown to indicate 2 enhancer regions. Putative KLF15 binding sites were identified based on consensus sequence, shown in vertical lines. A series of promoter sequence, and a 229bp fragment with a 21bp deletion from the 250bp fragment (-[ ]-) were cloned into pGL4.23 vector. 3T3 cells with shRNA knockdown of scrambled RNA (sh-Sc) or KLF15 (sh-Klf15) were transiently co-transfected with the luciferase vector for 48 hours before luminescence was measured. (n=4, *: p< 0.05 vs. sh-Sc, #: p<0.05 vs. sh-Sc transfected with empty vector, two-way ANOVA with Bonferroni correction). I, Working model.
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References

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