Title: Inhibition of S-adenosylhomocysteine hydrolase induces endothelial senescence via hTERT downregulation

Abstract

Background and aims: It has been established that endothelial senescence plays a critical role in the development of atherosclerosis. Elevated S-adenosylhomocysteine (SAH) level induced by inhibition of S-adenosylhomocysteine hydrolase (SAHH) is one of the risk factors of atherosclerosis; however, the interplay between endothelial senescence and inhibition of SAHH is largely unknown. Methods: Human umbilical vein endothelial cells (HUVECs) after serial passage were used. SAHH-specific inhibitor adenosine dialdehyde (ADA) and SAHH siRNA treated HUVECs and SAHH+/-mice were used to investigate the effect of SAHH inhibition on endothelial senescence. Results: HUVECs exhibited distinct senescence morphology as HUVECs were passaged, together with a decrease in intracellular SAHH expression and an increase of intracellular SAH levels. SAHH inhibition by ADA or SAHH siRNA elevated SA β-gal activity, arrested proliferation, and increased the expression of p16, p21 and p53 in HUVECs and the aortas of mice. In addition, decreased expression of hTERT and reduced occupancy of H3K4me3 over the hTERT promoter region were observed following SAHH inhibition treatment. To further verify the role of hTERT in the endothelial senescence induced by SAHH inhibition, overexpression of hTERT plasmid vector under CMV promoter was constructed. The hTERT overexpression rescued the senescence phenotypes in endothelial cells induced by the SAHH inhibition. Conclusions: SAHH inhibition induces endothelial senescence via the downregulation of hTERT expression, which is associated with attenuated histone methylation over the hTERT promoter region.

Biography

Wenhua Ling is a professor of School of Public Health, Sun Yat-sen University, a doctoral supervisor, director of the Institute of Preventive Medicine, School of Public Health, Sun Yat-sen University, the director, key Laboratory of Nutrition, Diet and Health, Guangdong Province, a member of the 6th and 7th Disciplinary Review Group of the degrees Committee of the State Council, "National Distinguished Young Scholar" winner, the instructor of 100 excellent doctoral theses in China, and he is also an excellent teacher in China. He also published research papers as newsletter or the first author in international authoritative academic journals such as Circulation, Circ Res, Hepatology, JCI, Diabetes Care, Am J Clin Nutr, Heart,Clin Chem, ATVB, Cardiovasc Res, J Lipid Res, J Biol Chem, J Nutr., etc.