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Single-Cell Transcriptomics Reveals the Immune Pathogenesis of Isolated Coronary Arteritis Presenting as Refractory
Miao Yu1, Yu Jiang2, Ji Huang3
1Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, Beijing, China; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.
Abstract:
The aim of the present study was to elucidate the cellular and molecular mechanisms underlying refractory recurrent in-stent restenosis (RISR), thereby facilitating the identification of potential therapeutic targets. Coronary blood samples were obtained from culprit lesions of patients with RISR and non-ISR controls and subjected to single-cell RNA sequencing to comprehensively characterize immune cell heterogeneity and identify pathogenic signaling pathways. Key molecular mechanisms were validated in independent clinical samples using flow cytometry, monocyte-vascular smooth muscle cell (VSMC) coculture systems, and in vitro functional assays. Causality was further assessed using a monocyte-specific Fos knockdown mouse model of carotid wire injury to evaluate its role in vascular remodeling. Results revealed a pronounced inflammatory immune signature in RISR, with marked upregulation of activator protein-1 (AP-1) gene expression and transcriptional activity in monocytes as a central feature. Upstream mechanistic analyses identified the CCL5-CCR1/p38 MAPK axis as a key driver of AP-1 activation, promoting proinflammatory cytokine release and inducing a proliferative phenotypic switch in VSMCs. In vivo, monocyte-specific Fos knockdown significantly attenuated neointimal hyperplasia and luminal stenosis following vascular injury. Targeting monocyte AP-1 signaling may represent a novel therapeutic strategy for refractory restenosis driven by localized coronary inflammation.
