Department of Chemistry, University of Texas at Austin (E.H.S.).
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, IN (Z.L.).
Arterioscler Thromb Vasc Biol. 2023 Sep;43(9):1626-1635. doi: 10.1161/ATVBAHA.122.318684. Epub 2023 Jun 29.
Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core.
Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis.
Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap.
Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.
碳水化合物、脂质和氨基酸代谢的损伤导致斑块不稳定的特征。然而，这些损伤在动脉粥样硬化中的发生部位在很大程度上尚不清楚。因此，我们试图描述纤维帽和坏死核心内稳定和不稳定动脉粥样硬化中代谢物的空间分布。
根据 Stary 分类量表对 9 个不匹配个体的动脉粥样硬化组织标本进行评分，并将其分为稳定和不稳定的动脉粥样硬化斑块。对这些样本进行质谱成像后，我们鉴定出超过 850 个与代谢物相关的峰。使用 MetaboScape、METASPACE 和人类代谢组数据库，我们对其中 170 个代谢物进行了准确注释，发现其中 60 多个代谢物在稳定和不稳定的动脉粥样硬化斑块之间存在差异。然后，我们将这些结果与比较稳定和不稳定人类动脉粥样硬化的 RNA 测序数据集进行整合。
将我们的质谱成像结果与 RNA 测序数据集整合后，我们发现与脂质代谢和长链脂肪酸相关的途径在稳定斑块中富集，而活性氧、芳香族氨基酸和色氨酸代谢在不稳定斑块中增加。此外，酰基肉碱和酰基甘油在稳定斑块中增加，而色氨酸代谢物在不稳定斑块中富集。评估稳定斑块的空间差异显示，在坏死核心中存在乳酸，而在纤维帽中丙酮酸升高。在不稳定斑块中，纤维帽中 5-羟色氨酸乙酸盐富集。
我们的工作代表了定义人类动脉粥样硬化斑块不稳定相关代谢途径图谱的第一步。我们预计这将是一个有价值的资源，并为心血管疾病的研究开辟新的途径。
