Inhibition of Class I and II HDACs has been reported to blunt pressure-overload induced LV hypertrophy. For example, Class I and II HDACs play an important role in the development of pathophysiological cardiac remodeling. Mounting evidence demonstrates a distinct role among different classes of HDACs. HDACs are classified into Classes I to IV. Sirt1 belongs to the Class III HDAC category. One possible mechanism by which Sirt1 confers cardioprotection by epigenomic modification in the myocardium is suppression of pathophysiological LV hypertrophy. Because various types of proteins seem to be a target of Sirt1-mediated deacetylation, most previous studies have focused not on histones, but on other functional proteins, such as transcription factors, anti-oxidative enzymes, and key enzymes in metabolic pathways, which activity might be regulated by direct deacetylation in the cardiovascular system.
However, it is still unknown whether histone deacetylation by Sirt1 plays any roles in the cardioprotective effects of CR via transcriptional regulation of specific genes. Increasing evidence demonstrates that cardiac Sir1 is essential for the development of CR-induced cardiovascular protection. Our studies showed that cardiac Sirt1 is activated during CR, based on evidence that Sir1 expression levels in the nuclear fraction were enhanced by CR and were associated with the decrease in acetyl-histone H3 levels determined by using antibodies detecting acetylated status at H3K9 and H3K14. These findings indicate the linkage between Sirt1 deacetylase function not only with regard to the regulation of specific proteins and decreased gene expression but also in terms of repression of specific loci and heterochromatin maintenance. Sirt1 mediates deacetylation of histone H4 at lysine 16 (H4K14) and histone H3 at lysine 9 (H3K9) leading to increased levels of trimethylation of H3K9, histone H1 recruitment, facilitating heterochromatin formation. Sirt1 plays a role in the establishment and maintenance of heterochromatin as a function of aging and CR. Sir2 HDAC activity is enhanced by NAD + levels when glucose is limited, and mutation of Sir2 abrogated protective effects of CR by reducing glucose in medium to increase cell span in yeast. Similar observations were reported in Caenorhabditis elegans and flies. The first robust observations regarding epigenetic mechanisms in lifespan modification were based on studies using yeast models indicating that increased expression of the Sir2 gene, which exhibits HDAC activity, extended lifespan.
Histones are acetylated by histone acetyl transferases (HATs) and deacetylated by histone deacetylases (HDACs). Histone acetylation and deacetylation are, in general, thought to result in euchromatin (transcriptional activation) and heterochromatin (transcriptional repression) states, respectively. Ken Shinmura, in Nutritional Epigenomics, 2019 3.2.1 Histone modification by CRĪcetylation is one of the most studied histone modifications in the context of aging research.