Epigenetic modulation of sirt1 and sirt6 in cardiovascular diseases: unraveling autophagy regulation and endothelial function

Abstract Background Heart failure (HF) and cardiovascular diseases (CVD) still represent major causes of death. Dysmetabolic conditions led by epigenetic alterations play a major role as CVD triggers, expecially those related to the modulation and control of autophagy during the remodelling in HF. Accordingly, several studies have strengthened the role of epigenetics in regulating both cardiac/endothelial phenotype and function, demonstrating how sirtuins, a well-acknowledged family of histone deacetylase, can conjunct the control of cardiac fibrosis, angiogenesis and induction of autophagy. However, this link remains to be fully clarified and explored. Thus, novel drugs targeting autophagy trough epigenetic mechanisms are considered appealing as targets from a pharmacological standpoint in CVD. Purpose This project aims to develop and test two epigenetic modulators and allosteric activators targeting SIRT1 and -6 to further elucidate their role in autophagy regulation and in cardiac/endothelial biology. Methods Chemical synthesis of SIRT1 and SIRT6 activator isoform (SRT2104 and MDL800). Evaluation of epigenetic modulation (H3 histone acetylation H3K9) of endothelial cells (HUVEC). HUVEC survival, angiogenic and autophagy activity were assessed undergo hyperglycemic or hypoxic stress, co-treatment with the selected compounds. Results The specific activator of SIRT-1 (SRT2104) and SIRT-6 (MDL800) show epigenetic activity as they induce the deacetylation of histone H3 on lysine 9. Endothelial cell viability is not influenced by the treatment with both modulators in hyperglycemia and upon hypoxic condition. In HUVEC cultures underwent to hyperglycemia-based stress, both molecules can activate autophagy with an increase in LC3 II protein (1,4-fold HG SRT2104 and 2,8-fold HG MDL800), compared to control.The treatment with SRT2104 enhances HUVEC tube formation, suggesting the increased functional angiogenic ability even in presence of high levels of glucose. Interestingly, the treatment with SRT2104 impacts the transcriptional levels of other members of the sirtuins family, by increasing SIRT-2, 3 and 5. In conclusion, the epigenetic activators SRT2104 and MDL800 have a beneficial effect on endothelial cells by enhancing the autophagic process and stimulate neoangiogenesis.The implementation of these results will attempt to understand to what extent epigenetic drugs such as sirtuin activators, could boost the more pleiotropic and less targeted effects of the current cardiovascular drugs, and to evaluate their functional and phenotype-driven drug refinement.