Abstract
BACKGROUND AND AIMS: The imbalance of carotid plaque stability is a key cause of acute cardiovascular and cerebrovascular events. Lipid metabolism disorder and endoplasmic reticulum stress (ERS) are both involved in the progression of atherosclerotic plaque. This study aims to reveal the role and molecular mechanism of abnormal phosphatidylcholine metabolism in ERS-induced carotid plaque instability, and to provide theoretical basis for plaque stabilization intervention. METHODS: With carotid plaques intima-media specimens as the research object, by HE staining is divided into a stable plaque group (group S) and unstable plaque group (U); The differences of metabolic profiles between the two groups were analyzed by principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The differential metabolites were screened by cluster heat map and volcano map. Metabolic pathway enrichment analysis and IPA pathway analysis were used to identify key pathways. Finally, Western blot and RT-qPCR were used to verify the protein and mRNA expression levels of key molecules in ERS pathway. RESULTS: Two groups of baseline characteristics have no statistical difference (P > 0.05); PCA and OPLS-DA showed that the metabolic profiles of group S and group U were significantly separated. A total of 198 potential biomarkers were identified. Among them, changes in phospholipid metabolites (including phosphatidylcholine) were significant, and these are the core markers for differentiating plaque stability. Metabolic pathway enrichment analysis showed that glycerophospholipid metabolic pathway was the key core pathway regulating plaque stability. The protein and mRNA expressions of key molecules of ERS pathway (GRP78, ATF6, PERK, CHOP and IRE1) in group U were significantly higher than those in group S. CONCLUSION: Abnormal metabolism of phosphatidylcholine can drive the transformation of carotid plaques to an unstable phenotype by activating the ER stress (ERS) pathway (especially the PERK/CHOP branch pathway); this study verified the association mechanism between abnormal phosphatidylcholine metabolism and the activation of the ER stress pathway and the occurrence of unstable carotid plaques, providing experimental evidence for the study of the mechanism of unstable carotid plaques and the formulation of targeted clinical intervention strategies.