Integrated human carotid plaque transcriptomics and macrophage perturbation link BCAP31 to endoplasmic reticulum stress, inflammation, and apoptosis
- 1epartment of Cardiology, Wenzhou Central Hospital, Wenzhou, China
Abstract
BackgroundAtherosclerotic plaque progression couples chronic inflammation to dysregulated cell survival, but the cellular context and regulatory role of endoplasmic reticulum (ER)-associated death responses in human carotid disease remain incompletely resolved.MethodsWe integrated paired bulk transcriptomes from 32 carotid plaque and macroscopically intact tissue pairs, laser-captured macrophages from five ruptured and six stable plaques, whole-plaque transcriptomes from 27 intraplaque-hemorrhage and 16 non-hemorrhage lesions, and single-cell RNA sequencing from three patients with matched atherosclerotic core and proximal adjacent tissue. BCAP31 was evaluated by siRNA-mediated depletion in oxidized low-density lipoprotein (oxLDL)-exposed THP-1-derived macrophages, with PCR, immunofluorescence, ELISA, apoptosis assays, and 4-phenylbutyrate treatment.ResultsPaired bulk analysis showed coordinated increases in apoptosis, ferroptosis, pyroptosis, necroptosis, inflammasome, inflammatory-response, and TNF/NF-κB programs. Ruptured plaque macrophages showed increases in ferroptosis, pyroptosis, and necroptosis scores, whereas intraplaque-hemorrhage plaques showed broader activation across all prespecified programs. Patient-level single-cell pseudobulk analysis localized a directionally consistent increase in BCAP31 to macrophages, although the estimate did not remain significant after transcriptome-wide correction in the three-patient dataset. Cross-sectional state ordering placed higher BCAP31 expression toward plaque-enriched HLA-C1QC, APOC1-SPP1-remodeling, and SPP1-lipid-loaded macrophage states, while predicted macrophage-to-vascular-wall SPP1 signaling increased in all three patient pairs. BCAP31 was also increased in paired plaque, rupture-macrophage, and intraplaque-hemorrhage cohorts and belonged to a plaque-associated coexpression module. In macrophages derived from THP-1 cells and treated with oxLDL, BCAP31 knockdown increased ER-stress transcripts, nuclear DDIT3, inflammatory cytokine expression and release, and Annexin V-positive apoptosis. The chemical chaperone 4-phenylbutyrate attenuated these effects.ConclusionHuman plaque transcriptomics and macrophage perturbation support a stress-adaptive role for BCAP31 in ER-stress-associated inflammation and apoptosis. Increased tissue expression and the adverse effects of depletion indicate that plaque-associated upregulation may reflect a compensatory response.
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BibTeX
@article{wang2026integrated,
title = {{Integrated human carotid plaque transcriptomics and macrophage perturbation link BCAP31 to endoplasmic reticulum stress, inflammation, and apoptosis}},
author = {Yunlong Wang and Bin Lin and Shanjiang Chen and Jianjian Yang and Anwu Huang},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1970662},
url = {https://doi.org/10.3389/fcell.2026.1970662},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrated human carotid plaque transcriptomics and macrophage perturbation link BCAP31 to endoplasmic reticulum stress, inflammation, and apoptosis
AU - Yunlong Wang
AU - Bin Lin
AU - Shanjiang Chen
AU - Jianjian Yang
AU - Anwu Huang
PY - 2026
DA - 2026/10/23
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1970662
UR - https://doi.org/10.3389/fcell.2026.1970662
AB - BackgroundAtherosclerotic plaque progression couples chronic inflammation to dysregulated cell survival, but the cellular context and regulatory role of endoplasmic reticulum (ER)-associated death responses in human carotid disease remain incompletely resolved.MethodsWe integrated paired bulk transcriptomes from 32 carotid plaque and macroscopically intact tissue pairs, laser-captured macrophages from five ruptured and six stable plaques, whole-plaque transcriptomes from 27 intraplaque-hemorrhage and 16 non-hemorrhage lesions, and single-cell RNA sequencing from three patients with matched atherosclerotic core and proximal adjacent tissue. BCAP31 was evaluated by siRNA-mediated depletion in oxidized low-density lipoprotein (oxLDL)-exposed THP-1-derived macrophages, with PCR, immunofluorescence, ELISA, apoptosis assays, and 4-phenylbutyrate treatment.ResultsPaired bulk analysis showed coordinated increases in apoptosis, ferroptosis, pyroptosis, necroptosis, inflammasome, inflammatory-response, and TNF/NF-κB programs. Ruptured plaque macrophages showed increases in ferroptosis, pyroptosis, and necroptosis scores, whereas intraplaque-hemorrhage plaques showed broader activation across all prespecified programs. Patient-level single-cell pseudobulk analysis localized a directionally consistent increase in BCAP31 to macrophages, although the estimate did not remain significant after transcriptome-wide correction in the three-patient dataset. Cross-sectional state ordering placed higher BCAP31 expression toward plaque-enriched HLA-C1QC, APOC1-SPP1-remodeling, and SPP1-lipid-loaded macrophage states, while predicted macrophage-to-vascular-wall SPP1 signaling increased in all three patient pairs. BCAP31 was also increased in paired plaque, rupture-macrophage, and intraplaque-hemorrhage cohorts and belonged to a plaque-associated coexpression module. In macrophages derived from THP-1 cells and treated with oxLDL, BCAP31 knockdown increased ER-stress transcripts, nuclear DDIT3, inflammatory cytokine expression and release, and Annexin V-positive apoptosis. The chemical chaperone 4-phenylbutyrate attenuated these effects.ConclusionHuman plaque transcriptomics and macrophage perturbation support a stress-adaptive role for BCAP31 in ER-stress-associated inflammation and apoptosis. Increased tissue expression and the adverse effects of depletion indicate that plaque-associated upregulation may reflect a compensatory response.
SN - 2296-634X
ER -