Vitamin D3 Suppresses Human Cytomegalovirus-Induced Vascular Endothelial Apoptosis via Rectification of Paradoxical m6A Modification of Mitochondrial Calcium Uniporter mRNA, Which Is Regulated by METTL3 and YTHDF3

Abstract

Human cytomegalovirus (HCMV) infection can induce apoptosis of vascular endothelial cells, which may be the most important element of development and progression of reported atherosclerosis caused by HCMV. As there are no specific drugs to clear HCMV infection, exploration of relevant drugs and mechanisms that can intervene in HCMV-induced atherosclerosis is urgently needed. The present study confirmed that vitamin D3 protected vascular endothelial cells from HCMV-induced apoptosis by inhibiting endoplasmic reticulum (ER) and mitochondrial apoptosis pathway. Mechanistically, HCMV infection could induce aberrantly elevated m6A modification, especially the increases of methyltransferases-“writers” (METTL3) and m6A binding proteins-“readers” (YTHDF3). METTL3 methylates mitochondrial calcium uniporter (MCU), the main contributor to HCMV-induced apoptosis of vascular endothelial cells, at three m6A residues in the 3′-UTR, which promotes the association of the YTHDF3 with methylated MCU mRNA and subsequently increases the translation and expression of MCU. Further analysis shows that ALKBH5 is the demethylases-“eraser” of MCU mRNA, which can negatively regulate the m6A modification process of MCU. Conversely, vitamin D3 downregulated the METTL3 by inhibiting the activation of AMPK, thereby inhibiting the m6A modification of MCU and cell apoptosis. Our findings extend the understanding of m6A driven machinery in virus-induced vascular endothelium damage and highlight the significance of vitamin D3 in the intervention of HCMV-induced atherosclerosis.

Ultrasound Assessment of Carotid Intima-Media Thickness: Comparison between Diabetes and Nondiabetes Subjects, and Correlation with Serum Vitamin D

“…Zhu et al attributed the protective efect of vitamin D3 against atherosclerosis to the hypothesis that human cytomegalovirus infection can trigger vascular endothelial cell apoptosis, which is the most important factor for the development and progression of atherosclerosis, and this vitamin causes inhibition of endoplasmic reticulum and mitochondrial apoptosis pathway [20].…”

M6A modification in cardiovascular disease: With a focus on programmed cell death

“…During the development of human cytomegalovirus-infected atherosclerosis, vitamin D3 can negatively regulate METTL3, inhibit human cytomegalovirus-induced increase in m 6 A methylation of mitochondrial calcium uniporter (MCU) in a YTHDF3-dependent manner, thereby ameliorating cell apoptosis and exerting its endothelial protective function. 133 The latest relevant research demonstrated that exercising training could mediate higher m 6 A levels by down-regulating FTO and reducing myocyte apoptosis, thereby ameliorating myocardial phenotypes in heart failure with preserved ejection fraction. This heralds that FTO acts as a potential therapeutic target for the regulation of cardiomyocyte function.…”

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension

“…Elevation of C-C motif chemokine receptor 10 (CCR10) decreases m 6 A methylation, promoting endothelial injury [ 25 ]. Similarly, human cytomegalovirus accelerates endothelial apoptosis through METTL3 and YTHDF3-mediated m 6 A modification [ 26 ]. Kong et al recently identified that m 6 A methylation on TRPC6 enhances hypoxia-mediated EndMT in rat PAECs through activating calcineurin/NFAT signaling [ 27 ].…”