Objective To investigate the effects of S-adenosyl homocysteine hydrolase (SAHH) overexpression on high fat and methionine induced atherosclerosis (AS). Methods ApoE-/- mice were fed a high-fat, high-methionine diet, with adenovirus-mediated SAHH overexpression intervention. The changes in body weight, food intake, blood lipid profiles, methionine metabolism indicators [(S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), homocysteine (Hcy) levels, and SAM/SAH ratio)] were observed. Hematoxylin and eosin (HE) and Oil Red O staining were used to evaluate the aortic sinus AS plaque size. Immunofluorescence staining and chemiluminescence staining were used to assess inflammation, cell proliferation, and oxidative stress in the aortic sinus. RNA sequencing was used to explore the impact of SAHH overexpression on key signaling pathways associated with AS. Results Compared to the control group, the SAHH overexpression group showed significantly lower plasma levels of SAH [(53.71 ± 5.43) nmol/L vs (31.79 ± 4.67 nmol/L) ] and SAM [(146.65±6.21) nmol/L vs (113.22±8.74) nmol/L), while the SAM/SAH ratio (2.76 ± 0.32) vs (3.61 ± 0.59) and Hcy [(10.58±2.94 ) μmol/L vs (14.87±2.36) μmol/L)] were significantly higher. The relative area of aortic sinus atherosclerotic plaques (0.19±0.07 vs 0.16±0.05) significantly decreased. Inflammation and cell proliferation markers, including cluster of differentiation 68 (CD68), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), Ki-67 antigen (Ki-67), and proliferating cell Nuclear Antigen (PCNA), were reduced. The average fluorescence intensity measured by dihydroethidium (DHE) staining was significantly decreased. Transcriptome analysis indicated that SAHH overexpression downregulated pro-inflammatory genes [interleukin-1 beta(IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) ] and upregulated anti-inflammatory, antioxidant, and anti-proliferative genes (peroxisome proliferator-activated receptor alpha (Pparα), heme oxygenase 1 (Hmox1), alpha-smooth muscle actin(Acta2) expression. KEGG analysis revealed significant enrichment of cytokine-cytokine receptor interaction genes. Conclusion SAHH overexpression exerts a protective action against high fat and methionine induced atherosclerosis.
Key words
SAH hydrolase /
methionine metabolism disorder /
atherosclerosis
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References
[1] Li J, Fu X, Yang R, et al. Atherosclerosis vascular endothelial secretion dysfunction and smooth muscle cell proliferation[J]. J Healthc Eng, 2022,2022:9271879.
[2] Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study[J]. J Am Coll Cardiol, 2020, 76: 2982–3021.
[3] Barquera S, Pedroza-Tobías A, Medina C, et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease[J]. Arch Med Res, 2015, 46: 328–338.
[4] Wang L, Hu B, Pan K, et al. SYVN1-MTR4-MAT2A signaling axis regulates methionine metabolism in glioma cells[J]. Front Cell Dev Biol, 2021, 9: 633259.
[5] Martínez Y, Li X, Liu G, et al. The role of methionine on metabolism, oxidative stress, and diseases[J]. Amino Acids, 2017, 49: 2091–2098.
[6] Shen W, Gao C, Cueto R, et al. Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling[J]. Redox Biol, 2020, 28: 101322.
[7] Luo X, Xiao Y, Song F, et al. Increased plasma S-adenosyl-homocysteine levels induce the proliferation and migrtion of VSMCs through an oxidative stress-ERK1/2 pathway in apoE(-/-) mice[J]. Cardiovasc Res, 2012, 95: 241-250.
[8] Liu C, Wang Q, Guo H, et al. Plasma S-adenosylhomocy-steine is a better biomarker of atherosclerosis than homocysteine in apolipoprotein E-deficient mice fed high dietary methionine[J]. J Nutr, 2008, 138: 311–315.
[9] Tehlivets O, Malanovic N, Visram M, et al. S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system[J]. Biochim Biophys Acta, 2013, 1832: 204–215.
[10] Xiao Y, Zhang Y, Wang M, et al. Plasma S-adenosylho-mocysteine is associated with the risk of cardiovascular events in patients undergoing coronary angiography: a cohort study[J]. Am J Clin Nutr, 2013, 98: 1162–1169.
[11] Xiao Y, Xia J, Cheng J, et al. Inhibition of S-adenosylhomocysteine hydrolase induces endothelial dysfunction via epigenetic regulation of p66shc-mediated oxidative stress pathway[J]. Circulation, 2019, 139: 2260–2277.
[12] Halperin RO, Sesso HD, Ma J, et al. Dyslipidemia and the risk of incident hypertension in men[J]. Hypertension, 2006, 47: 45–50.
[13] Ma X, Deng J, Han L, et al. Single-cell RNA sequencing reveals B cell-T cell interactions in vascular adventitia of hyperhomocysteinemia-accelerated atherosclerosis[J]. Protein Cell, 2022, 13: 540–547.
[14] Xu L, Hao H, Hao Y, et al. Aberrant MFN2 transcription facilitates homocysteine-induced VSMCs proliferation via the increased binding of c-Myc to DNMT1 in atherosclerosis[J]. J Cell Mol Med, 2019, 23: 4611–4626.
[15] Lu SS, Xie J, Su CQ, et al. Plasma homocysteine levels and intracranial plaque characteristics: association and clinical relevance in ischemic stroke[J]. BMC Neurol, 2018, 18: 200.
[16] Klimek A, Nowakowska A, Kletkiewicz H, et al. Bidirectional effect of repeated exposure to extremely low-frequency electromagnetic field (50 Hz) of 1 and 7 mT on oxidative/antioxidative status in rat's brain: the prediction for the vulnerability to diseases[J]. Oxid Med Cell Longev, 2022, 1031211.
[17] Dinarello CA.Interleukin-1 in the pathogenesis and treatment of inflammatory diseases[J]. Blood, 2011, 117: 3720–3732.
[18] Deng X, Liang C, Qian L, et al. miR-24 targets HMOX1 to regulate inflammation and neurofunction in rats with cerebral vasospasm after subarachnoid hemorrhage[J]. Am J Transl Res, 2021, 13: 1064–1074.
[19] Moss JW, Ramji DP.Cytokines: roles in atherosclerosis disease progression and potential therapeutic targets[J]. Future Med Chem, 2016, 8: 1317–1330.
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