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. 2018 Jul 2;9:2560. doi: 10.1038/s41467-018-04994-z

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — TGF-β/miR-29/H4K20me3 is involved in aging-associated cardiac dysfunction. a RT-qPCR to measure miR-29 expression, normalized to U6, in murine hearts (n = 4 per age) of the indicated ages (1-month-old, 1 m; 2-month-old, 2 m; 1-year-old, 1 y; 1.5-year-old, 1.5 y; 2-year-old, 2 y). b Western blot for H4K20 methylation in hearts of the indicated ages. c RT-qPCR to examine miR-29 expression in hearts of 1 y and 2 y mice, fed with DMSO or E-616452. The error bars represent the s.d obtained from triplicate independent experiments. d Western blot for H4K20 methylation in hearts from c. e, f Mice (2 m) fed with DMSO (n = 4) or A-196 (n = 4) and mice (1 y) treated with DMSO (n = 8) or E-616452 (n = 8) were subjected to cardiac function analysis using an echocardiographic imaging system (VisualSonics Vevo 2100, USA). EF (e) represents the ejection fraction of left ventricular flow, whereas E/A (f), the peak early filling (E-wave)/late diastolic filling (A-wave), represents the mitral flow rate. Representative images are shown in Supplementary Fig. 7e, f. The error bars represent the s.d. of the mean values. g, h RT-qPCR analysis of Ryr2 (g) and Myh7 (h) expression in cardiomyocytes isolated from mice of the indicated ages. i SA-β-gal staining of cardiomyocytes from mice as in g. The lower panel shows the magnified cells enclosed by red rectangular boxes in the images in the upper panel. Scale bar = 20 μm. The plot shows the proportion of SA-β-gal-stained cells among the different age groups. j Western blot for the indicated proteins in cells from i. k RT-qPCR for miR-29 expression in isolated cells from i. l Western blot for H4K20 methylations in cells from f. m Mechanisms proposed in this study. When cells undergo senescence-inducing stimuli, such as oxidative stress, TGF-β signaling is activated and serves as the signal transducer that promotes acute accumulation of miR-29, which in turn results in suppression of Suv4-20h and reduction in H4K20me3 abundance, leading to defective DNA damage repair and impaired maintenance of genome stability, and thus accelerating cellular senescence. Gapdh, H3 and α-tubulin were loading controls. Two-tailed unpaired Student’s t-tests, *p < 0.05, **p < 0.01, ***p < 0.001