动脉粥样硬化斑块表观遗传年龄加速预示预后不良，并与人类内皮-间充质转化相关。
Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans.
作者信息
Diez Benavente Ernest, Hartman Robin J G, Sakkers Tim R, Wesseling Marian, Sloots Yannicke, Slenders Lotte, Boltjes Arjan, Mol Barend M, de Borst Gert J, de Kleijn Dominique P V, Prange Koen H M, de Winther Menno P J, Kuiper Johan, Civelek Mete, van der Laan Sander W, Horvath Steve, Onland-Moret N Charlotte, Mokry Michal, Pasterkamp Gerard, den Ruijter Hester M
机构信息
Laboratory of Experimental Cardiology (E.D.B., R.J.G.H., T.R.S., Y.S., M.M., H.M.d.R.), University Medical Center Utrecht, Utrecht University, the Netherlands.
Central Diagnostic Laboratory (M.W., L.S., A.B., S.W.v.d.L., M.M., G.P.), University Medical Center Utrecht, Utrecht University, the Netherlands.
出版信息
Arterioscler Thromb Vasc Biol. 2024 Jun;44(6):1419-1431. doi: 10.1161/ATVBAHA.123.320692. Epub 2024 Apr 18.
BACKGROUND
Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events.
METHODS
Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells.
RESULTS
Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, -2.2 [interquartile range, -4.3 to 2.2] years) and 68 years in males (median EAA, -0.3 [interquartile range, -2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; =0.0034) and adjusted multivariate model (hazard ratio, 1.56; =0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; =0.018) and of plaque hemorrhage (hazard ratio, 1.7; =0.02). Single-cell RNA sequencing in plaque samples from 46 patients in the same cohort revealed smooth muscle and endothelial cells as important cell types in plaque EAA. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally confirmed by -triggered endothelial-to-mesenchymal transition inducing rapid epigenetic aging in coronary endothelial cells.
CONCLUSIONS
Plaque EAA is a strong and independent marker of poor outcome in patients with severe atherosclerosis. Plaque EAA was linked to mesenchymal endothelial and smooth muscle cells. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally validated. Epigenetic aging mechanisms may provide new targets for treatments that reduce atherosclerosis complications.
背景
表观遗传年龄估计器（时钟）可预测人类死亡风险。然而，尚不清楚动脉粥样硬化斑块的表观遗传年龄是否可预测心血管事件风险。
方法
利用Athero-Express动脉内膜切除术队列中人类颈动脉粥样硬化斑块（n = 485）和血液（n = 93）的全基因组DNA甲基化来计算表观遗传年龄加速（EAA）。EAA与临床特征、斑块组织学及未来心血管事件（n = 136）相关联。我们研究了全基因组DNA甲基化以及大量和单细胞转录组学，以揭示斑块EAA的分子机制。我们在原代人冠状动脉内皮细胞中进行体外实验，通过实验证实了我们的计算机模拟结果。
结果
患有严重动脉粥样硬化的男性和女性患者的实际年龄中位数为69岁。女性的表观遗传年龄中位数为65岁（EAA中位数为-2.2[四分位间距，-4.3至2.2]岁），男性为68岁（EAA中位数为-0.3[四分位间距，-2.9至3.8]岁）。患有糖尿病和高体重指数的患者斑块EAA更高。在Cox回归模型的3年随访中，斑块EAA升高预测未来事件（单变量风险比，1.7；P = 0.0034），在调整后的多变量模型中（风险比，1.56；P = 0.02）。斑块EAA独立于血液EAA（风险比，1.3；P = 0.018）和斑块出血（风险比，1.7；P = 0.02）预测结局。对同一队列中46例患者的斑块样本进行单细胞RNA测序显示，平滑肌细胞和内皮细胞是斑块EAA中的重要细胞类型。内皮向间充质转化与EAA相关，在冠状动脉内皮细胞中，TGF-β触发的内皮向间充质转化诱导快速表观遗传衰老，通过实验证实了这一点。
结论
斑块EAA是严重动脉粥样硬化患者不良结局的一个强大且独立的标志物。斑块EAA与间充质、内皮和平滑肌细胞相关。内皮向间充质转化与EAA相关，这一点已通过实验验证。表观遗传衰老机制可能为减少动脉粥样硬化并发症的治疗提供新靶点。
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