Cholecalciferol and metformin protect against lipopolysaccharide-induced endothelial dysfunction and senescence by modulating sirtuin-1 and protein arginine methyltransferase-1

• Published in: European journal of pharmacology 2021-12, Vol.912, p.174531-174531, Article 174531
• Main Authors: Raj, Vijay, Natarajan, Suganya, C, Marimuthu, Chatterjee, Suvro, Ramasamy, Mohankumar, Ramanujam, Ganesh Munuswamy, Arasu, Mariadhas Valan, Al-Dhabi, Naif Abdullah, Choi, Ki Choon, Arockiaraj, Jesu, Karuppiah, Kanchana
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; Arginine - analogs & derivatives; Arginine - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line; Cell senescence; Cellular Senescence - drug effects; Cholecalciferol - pharmacology; Endothelium - drug effects; Homocysteine - metabolism; Humans; Lipopolysaccharide; Lipopolysaccharides - toxicity; Metformin - pharmacology; Methylation - drug effects; NAD - metabolism; Nitric Oxide - metabolism; Protective Agents - pharmacology; Protein arginine methyltransferase-1; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; S-Adenosylmethionine - metabolism; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; sirtuin1; Telomerase - metabolism; Vitamin D Response Element
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174531

Endothelial cell activation through nuclear factor-kappa-B (NFkB) and mitogen-activated protein kinases leads to increased biosynthesis of pro-inflammatory mediators, cellular injury and vascular inflammation under lipopolysaccharide (LPS) exposure. Recent studies report that LPS up-regulated global methyltransferase activity. In this study, we observed that a combination treatment with metformin (MET) and cholecalciferol (VD) blocked the LPS-induced S-adenosylmethionine (SAM)-dependent methyltransferase (SDM) activity in Eahy926 cells. We found that LPS challenge (i) increased arginine methylation through up-regulated protein arginine methyltransferase-1 (PRMT1) mRNA, intracellular concentrations of asymmetric dimethylarginine (ADMA) and homocysteine (HCY); (ii) up-regulated cell senescence through mitigated sirtuin-1 (SIRT1) mRNA, nicotinamide adenine dinucleotide (NAD+) concentration, telomerase activity and total antioxidant capacity; and (iii) lead to endothelial dysfunction through compromised nitric oxide (NOx) production. However, these LPS-mediated cellular events in Eahy926 cells were restored by the synergistic effect of MET and VD. Taken together, this study identified that the dual compound effect inhibits LPS-induced protein arginine methylation, endothelial senescence and dysfunction through the components of epigenetic machinery, SIRT1 and PRMT1, which is a previously unidentified function of the test compounds. In silico results identified the presence of vitamin D response element (VDRE) sequence on PRMT1 suggesting that VDR could regulate PRMT1 gene expression. Further characterization of the cellular events associated with the dual compound challenge, using gene silencing approach or adenoviral constructs for SIRT1 and/or PRMT1 under inflammatory stress, could identify therapeutic strategies to address the endothelial consequences in vascular inflammation-mediated atherosclerosis. [Display omitted] •MET+VD reduced the LPS-induced SDM activity and protein arginine methylation by restoring the normal PRMT1 mRNA, ADMA & HCY.•MET+VD improved several senescence indicators such as endothelial cell cycle arrest, SIRT1 mRNA, telomerase activity and NAD+.•Identification of in silico VDRE sequence on PRMT1 suggests that vitamin D receptor could regulate PRMT1 transcription.•SIRT1 and PRMT1 can be potential targets for the combined effect in reducing the LPS-induced endothelial stress responses.