Sirtuin 2 Exerts Regulatory Functions on Radiation-Induced Myocardial Fibrosis in Mice by Mediating H3K27 Acetylation of Galectin-3 Promoter.

Abstract

Sirtuin 2 (SIRT2) and galectin-3 have been shown to protect the heart against fibrosis. However, their impacts on radiation-induced myocardial fibrosis (RIMF) remain to be elucidated. To deepen this understanding, the current study sought to explore the effects of SIRT2 and galectin-3 on RIMF and the underlying mechanisms. Galectin-3 knockout mice were obtained, and a radiation-induced heart damage (RIHD) mouse model was induced by local radiation exposure to the heart. Lentivirus transfection was then performed, and heart function, fibrosis of heart tissues, and levels of SIRT2, galectin-3, and fibrosis-related markers collagen type-I/-III and matrix metalloproteinase (MMP)2/MMP9 were respectively assessed by echocardiography, hematoxylin-eosin and Masson staining, reverse transcription-quantitative polymerase chain reaction, Western blot, and immunofluorescence staining. Additionally, Western blot and chromatin immunoprecipitation were used to test H3K27 acetylation levels and the binding of H3K27ac to galectin-3, respectively. After radiation exposure, heart tissues from the galectin-3 knockout mice had a smaller fibrotic area compared to normal mice, with reduced expression levels of collagen type-I/-III and MMP2/MMP9. SIRT2 was down-regulated and galectin-3 was up-regulated after RIHD treatment. The histone deacetylase inhibitor sirtinol promoted galectin-3 expression and H3K27 acetylation in a time-dependent manner, and increased H3K27ac enrichment in the galectin-3 promoter. Overexpression of SIRT2 down-regulated H3K27ac, collagen type-I/-III, and MMP2/MMP9 expression levels, and reduced the fibrotic area in mouse heart tissues. However, these effects were reversed by the additional overexpression of galectin-3. SIRT2 facilitates deacetylation of H3K27 to inhibit galectin-3 transcription, thus ameliorating RIMF in mice.