Name	Atherosclerosis
ICD	ICD-11: BD40

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	m6A driven machinery in virus-induced vascular endothelium damage and highlight the significance of vitamin D3 in the intervention of HCMV-induced atherosclerosis. 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. Vitamin D3 downregulated the METTL3 by inhibiting the activation of AMPK subunit alpha-1 (AMPK/PRKAA1), thereby inhibiting the m6A modification of MCU and cell apoptosis.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	AMPK signaling pathway			hsa04152
Cell Process	Cell apoptosis
In-vitro Model	hTERT-RPE1	Normal	Homo sapiens	CVCL_4388
	iHAEC	Normal	Homo sapiens	CVCL_C0EQ

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Knocking down METTL14 could inhibit the development of atherosclerosis in high-fat diet-treated APOE mice. After transfection with si-METTL14, the Apoptosis regulator Bcl-2 (BCL2) expression level and the viability of ox-LDL-incubated cells increased, whereas the apoptosis rate and the expressions of Bax and cleaved caspase-3 decreased. However, the effect of METTL14 knockdown was reversed by p65 overexpression.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	Apoptosis			hsa04210
Cell Process	Cell apoptosis
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
	EA.hy 926	Normal	Homo sapiens	CVCL_3901
In-vivo Model	The mice were randomly divided into control, Ad-sh-NC, and Ad-sh-METTL14 groups (10 mice per group). The mice in the control group were fed a normal diet, while the Ad-sh-NC and Ad-sh-METTL14 groups were fed a high-fat diet (20% fat and 0.25% cholesterol). Furthermore, 300 uL of constructed sh-NC or sh-METTL14 adenovirus was injected every 3 weeks into the caudal veins of mice from the Ad-sh-NC or Ad-sh-METTL14 groups, respectively. The constructed vectors were obtained from HanBio Technology Co., Ltd. (Shanghai, China). All mice were sacrificed after 24 weeks and the aortas were separated for further experiments.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	METTL14 promotes Forkhead box protein O1 (FOXO1) expression by enhancing its m6A modification and inducing endothelial cell inflammatory response as well as atherosclerotic plaque formation.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	FoxO signaling pathway			hsa04068
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
In-vivo Model	Mettl14-/+ mice are generated by mating wild-type mice (C57/BL6 background) with Mettl14-/+ mice. Mettl14-/+/APOE-/- healthy offspring mice are produced by heterozygous Mettl14-/+ mice and heterozygous APOE-/- mice by Mendelian ratios. APOE-/- mice and C57/BL6 mice were purchased from Model Animal Research Center of Nanjing (Nanjing, Jiangsu, China). All mice were housed in the Laboratory Animals Center of the Henan Provincial People's Hospital, with controlled temperature and humidity and a 12:12-hour dark-light cycle, and were provided water and mouse chow ad libitum.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques, Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-Kappa-B/Interleukin-6 (IL-6) signaling pathway.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	IL-17 signaling pathway			hsa04657
In-vitro Model	THP-1	Childhood acute monocytic leukemia	Homo sapiens	CVCL_0006
In-vivo Model	Mettl14 heterozygous mice (Mettl14-/+) were established from C57/BL6 mice by Cyagen Biosciences, Inc. (Suzhou, Jiangsu, China), using CRISPR/Cas9-based targeting and homology-directed repair. C57/BL6 and APOE-/- mice were purchased from Beijing Vital River Laboratory Animal Technology (Beijing, China). Mettl14-/+APOE-/- mice were generated by breeding Mettl14-/+ mice with APOE-/- mice. Eight- to 10-week-old male APOE-/- (WT) mice and Mettl14-/+APOE-/- (KO) mice were fed a high-cholesterol diet (D12108C, Opensource diets) for 12 weeks. Then, the mice were euthanized for further analysis.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	In the in vivo atherosclerosis model,partial ligation of the carotid artery led to plaque formation and up-regulation of METTL3 and NLRP1, with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NLRP1 up-regulation, and Krueppel-like factor 4 (KLF4) down-regulation. Collectively, it has demonstrated that METTL3 serves a central role in the atherogenesis induced by oscillatory stress and disturbed blood flow.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
In-vitro Model	MAEC	Normal	Mus musculus	CVCL_U411
	HUVEC-C	Normal	Homo sapiens	CVCL_2959

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	In the in vivo atherosclerosis model,partial ligation of the carotid artery led to plaque formation and up-regulation of METTL3 and NLRP1, with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NACHT, LRR and PYD domains-containing protein 3 (NLRP3) up-regulation, and KLF4 down-regulation. Collectively, it has demonstrated that METTL3 serves a central role in the atherogenesis induced by oscillatory stress and disturbed blood flow.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vitro Model	MAEC	Normal	Mus musculus	CVCL_U411
	HUVEC-C	Normal	Homo sapiens	CVCL_2959

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	In the in vivo atherosclerosis model,partial ligation of the carotid artery led to plaque formation and up-regulation of METTL3 and NACHT/LRR/PYD domains-containing protein 1 (NLRP1), with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NLRP3 up-regulation, and KLF4 down-regulation. Collectively, it has demonstrated that METTL3 serves a central role in the atherogenesis induced by oscillatory stress and disturbed blood flow.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vitro Model	MAEC	Normal	Mus musculus	CVCL_U411
	HUVEC-C	Normal	Homo sapiens	CVCL_2959

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques, Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the Nuclear factor NF-kappa-B p105 subunit (NF-Kappa-B/NFKB1)/IL-6 signaling pathway.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	IL-17 signaling pathway			hsa04657
In-vitro Model	THP-1	Childhood acute monocytic leukemia	Homo sapiens	CVCL_0006
In-vivo Model	Mettl14 heterozygous mice (Mettl14-/+) were established from C57/BL6 mice by Cyagen Biosciences, Inc. (Suzhou, Jiangsu, China), using CRISPR/Cas9-based targeting and homology-directed repair. C57/BL6 and APOE-/- mice were purchased from Beijing Vital River Laboratory Animal Technology (Beijing, China). Mettl14-/+APOE-/- mice were generated by breeding Mettl14-/+ mice with APOE-/- mice. Eight- to 10-week-old male APOE-/- (WT) mice and Mettl14-/+APOE-/- (KO) mice were fed a high-cholesterol diet (D12108C, Opensource diets) for 12 weeks. Then, the mice were euthanized for further analysis.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	METTL3 knockdown prevented Atherosclerosis progression by inhibiting JAK2/Signal transducer and activator of transcription 3 (STAT3) pathway via IGF2BP1.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	JAK-STAT signaling pathway			hsa04630
Cell Process	Cell proliferation and migration
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
In-vivo Model	The adeno-associated viruses (AAV) that could silence METTL3 (sh-METTL3) and the negative control adeno-associated viruses (sh-NC) were obtained from WZ Biosciences Inc. (Jinan, China). APOE-/- mice were randomly divided into AS + sh-NC and AS + sh-METTL3 groups. Each group contains five mice. Mice were fed with the standard diet for 1 week to acclimatize. After 1 week of acclimation, mice were challenged with a high-fat and high-cholesterol feed H10540 (Beijing HFK BIOSCIENCE Co., Ltd., Beijing, China). The formula of the H10540 feed was shown in Supplementary File S1. After 8 weeks of HFD feeding, sh-NC or sh-METTL3 adeno-associated virus serotype 9 (AAV9, 1012 viral genome copies per mouse) were respectively delivered into mice in AS + sh-NC or AS + sh-METTL3 group through tail vein injection. At 14 weeks after HDF feeding, mice fasted overnight.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	METTL3 knockdown prevented Atherosclerosis progression by inhibiting JAK2/Signal transducer and activator of transcription 3 (STAT3) pathway via IGF2BP1.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)		READER	Regulator Info
Target Regulation	Up regulation
Pathway Response	JAK-STAT signaling pathway			hsa04630
Cell Process	Cell proliferation and migration
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
In-vivo Model	The adeno-associated viruses (AAV) that could silence METTL3 (sh-METTL3) and the negative control adeno-associated viruses (sh-NC) were obtained from WZ Biosciences Inc. (Jinan, China). APOE-/- mice were randomly divided into AS + sh-NC and AS + sh-METTL3 groups. Each group contains five mice. Mice were fed with the standard diet for 1 week to acclimatize. After 1 week of acclimation, mice were challenged with a high-fat and high-cholesterol feed H10540 (Beijing HFK BIOSCIENCE Co., Ltd., Beijing, China). The formula of the H10540 feed was shown in Supplementary File S1. After 8 weeks of HFD feeding, sh-NC or sh-METTL3 adeno-associated virus serotype 9 (AAV9, 1012 viral genome copies per mouse) were respectively delivered into mice in AS + sh-NC or AS + sh-METTL3 group through tail vein injection. At 14 weeks after HDF feeding, mice fasted overnight.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Knocking down METTL14 could inhibit the development of atherosclerosis in high-fat diet-treated APOE mice. After transfection with si-METTL14, the bcl-2 expression level and the viability of ox-LDL-incubated cells increased, whereas the apoptosis rate and the expressions of Bax and cleaved caspase-3 decreased. However, the effect of METTL14 knockdown was reversed by Transcription factor p65 (RELA) overexpression.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Cell Process	Cell apoptosis
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
	EA.hy 926	Normal	Homo sapiens	CVCL_3901
In-vivo Model	The mice were randomly divided into control, Ad-sh-NC, and Ad-sh-METTL14 groups (10 mice per group). The mice in the control group were fed a normal diet, while the Ad-sh-NC and Ad-sh-METTL14 groups were fed a high-fat diet (20% fat and 0.25% cholesterol). Furthermore, 300 uL of constructed sh-NC or sh-METTL14 adenovirus was injected every 3 weeks into the caudal veins of mice from the Ad-sh-NC or Ad-sh-METTL14 groups, respectively. The constructed vectors were obtained from HanBio Technology Co., Ltd. (Shanghai, China). All mice were sacrificed after 24 weeks and the aortas were separated for further experiments.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	METTL3 knockdown prevented Atherosclerosis progression by inhibiting Tyrosine-protein kinase JAK2 (JAK2)/STAT3 pathway via IGF2BP1.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	JAK-STAT signaling pathway			hsa04630
Cell Process	Cell proliferation and migration
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
In-vivo Model	The adeno-associated viruses (AAV) that could silence METTL3 (sh-METTL3) and the negative control adeno-associated viruses (sh-NC) were obtained from WZ Biosciences Inc. (Jinan, China). APOE-/- mice were randomly divided into AS + sh-NC and AS + sh-METTL3 groups. Each group contains five mice. Mice were fed with the standard diet for 1 week to acclimatize. After 1 week of acclimation, mice were challenged with a high-fat and high-cholesterol feed H10540 (Beijing HFK BIOSCIENCE Co., Ltd., Beijing, China). The formula of the H10540 feed was shown in Supplementary File S1. After 8 weeks of HFD feeding, sh-NC or sh-METTL3 adeno-associated virus serotype 9 (AAV9, 1012 viral genome copies per mouse) were respectively delivered into mice in AS + sh-NC or AS + sh-METTL3 group through tail vein injection. At 14 weeks after HDF feeding, mice fasted overnight.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	METTL3 knockdown prevented Atherosclerosis progression by inhibiting Tyrosine-protein kinase JAK2 (JAK2)/STAT3 pathway via IGF2BP1.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)		READER	Regulator Info
Target Regulation	Up regulation
Pathway Response	JAK-STAT signaling pathway			hsa04630
Cell Process	Cell proliferation and migration
In-vitro Model	HUVEC-C	Normal	Homo sapiens	CVCL_2959
In-vivo Model	The adeno-associated viruses (AAV) that could silence METTL3 (sh-METTL3) and the negative control adeno-associated viruses (sh-NC) were obtained from WZ Biosciences Inc. (Jinan, China). APOE-/- mice were randomly divided into AS + sh-NC and AS + sh-METTL3 groups. Each group contains five mice. Mice were fed with the standard diet for 1 week to acclimatize. After 1 week of acclimation, mice were challenged with a high-fat and high-cholesterol feed H10540 (Beijing HFK BIOSCIENCE Co., Ltd., Beijing, China). The formula of the H10540 feed was shown in Supplementary File S1. After 8 weeks of HFD feeding, sh-NC or sh-METTL3 adeno-associated virus serotype 9 (AAV9, 1012 viral genome copies per mouse) were respectively delivered into mice in AS + sh-NC or AS + sh-METTL3 group through tail vein injection. At 14 weeks after HDF feeding, mice fasted overnight.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[8]
Response Summary	METTL14 increased the M6A modification of pri-miR-19a and promoted the processing of mature hsa-miR-19a-3p, thus promoting the proliferation and invasion of atherosclerotic vascular endothelial cells.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Cell Process	Cell migration and invasion
	Epithelial-mesenchymal transition
In-vitro Model	ASVEC cell line (Atherosclerotic vascular endothelial cells)

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[9]
Response Summary	Silencing METTL3 inhibited m6A level and decreased the binding of DGCR8 to pri-miR-375 and further limited hsa-miR-375-3p expression. METTL3-mediated m6A modification promoted VSMC phenotype transformation and made Atherosclerosis (AS) plaques more vulnerable via the miR-375-3p/PDK1 axis.
Responsed Disease	Atherosclerosis [ICD-11: BD40.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Focal adhesion			hsa04510
In-vitro Model	MOVAS (Mouse aortic vascular smooth muscle cell lines)
In-vivo Model	The normal group consisted of C57BL/6J mice on normal diet and the HFD group consisted of ApoE C57BL/6J mice on HFD (containing 10% lard oil, 4% milk powder, 2% cholesterol, and 0.5% sodium cholate). Four weeks after HFD feeding, the mice were injected with 200 ul lentivirus containing 1 × 10-/--/-8 TU (lentivirus carrying sh-METTL3 or sh-NC; designed and constructed by GENCHEM (Shanghai, China)) via tail vein. Six weeks after transfection, all mice were euthanized by a tail vein injection of 200 mg/kg pentobarbital sodium.

Ref 1	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. Front Microbiol. 2022 Mar 11;13:861734. doi: 10.3389/fmicb.2022.861734. eCollection 2022.
Ref 2	Methyltransferase-like 14 silencing relieves the development of atherosclerosis via m(6)A modification of p65 mRNA. Bioengineered. 2022 May;13(5):11832-11843. doi: 10.1080/21655979.2022.2031409.
Ref 3	METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications. Theranostics. 2020 Jul 11;10(20):8939-8956. doi: 10.7150/thno.45178. eCollection 2020.
Ref 4	Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-KappaB/IL-6 signaling pathway. Cell Mol Life Sci. 2022 May 22;79(6):311. doi: 10.1007/s00018-022-04331-0.
Ref 5	METTL3-dependent N(6)-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium. Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):e2025070118. doi: 10.1073/pnas.2025070118.
Ref 6	METTL14 mediated m6A modification to LncRNA ZFAS1/ RAB22A: A novel therapeutic target for atherosclerosis. Int J Cardiol. 2021 Apr 1;328:177. doi: 10.1016/j.ijcard.2020.12.002. Epub 2020 Dec 8.
Ref 7	N6-Methyladenosine Methyltransferase METTL3 Promotes Angiogenesis and Atherosclerosis by Upregulating the JAK2/STAT3 Pathway via m6A Reader IGF2BP1. Front Cell Dev Biol. 2021 Dec 7;9:731810. doi: 10.3389/fcell.2021.731810. eCollection 2021.
Ref 8	METTL14 regulates M6A methylation-modified primary miR-19a to promote cardiovascular endothelial cell proliferation and invasion. Eur Rev Med Pharmacol Sci. 2020 Jun;24(12):7015-7023. doi: 10.26355/eurrev_202006_21694.
Ref 9	Silencing METTL3 Stabilizes Atherosclerotic Plaques by Regulating the Phenotypic Transformation of Vascular Smooth Muscle Cells via the miR-375-3p/PDK1 Axis. Cardiovasc Drugs Ther. 2022 Jun 15. doi: 10.1007/s10557-022-07348-6. Online ahead of print.