ArticleArteriosclerosis, thrombosis, and vascular biology2023
Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Oleoylethanolamide enhances regulatory T Cell function to accelerate plaque regression in atherosclerosis via PPARα activation.The Journal of biological chemistry · 2026Article
- Progress in the Cross-Organ Biomarker oxLDL in Promoting Pathological Neovascular Diseases.Antioxidants (Basel, Switzerland) · 2026Review
- Review
- Decoding lysophosphatidic acid signaling in physiology and disease: mapping the multimodal and multinodal signaling networks.Signal transduction and targeted therapy · 2025Review
- Single-Cell Transcriptomics of Human Pericarotid Lymph Nodes Indicating Stability of Carotid Atherosclerotic Plaques.Journal of the American Heart Association · 2025Article
- Regulatory T cell and endothelial cell crosstalk.Nature reviews. Immunology · 2025Review
- Limited Proteolysis as a Regulator of Lymphatic Vessel Function and Architecture.International journal of molecular sciences · 2025Review
- Targeting Lysophosphatidic Acid Ameliorates Dyslipidemia in Familial Hypercholesterolemia.Research (Washington, D.C.) · 2025Article
- Characteristics and advances in signaling pathways, cellular communication, cell junctions, and oxidative stress in lymphedema.Frontiers in cell and developmental biology · 2025Review
- Regulatory T cells and macrophages in atherosclerosis: from mechanisms to clinical significance.Frontiers in immunology · 2024Review
- Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets.Frontiers in immunology · 2024Review
- Calpain and Cardiometabolic Diseases.International journal of molecular sciences · 2023Review
- LFA-1/ICAM-1 Adhesion Pathway Mediates the Homeostatic Migration of Lymphocytes from Peripheral Tissues into Lymph Nodes through Lymphatic Vessels.Biomolecules · 2023Article
- How Lymphatic Endothelial Cells Destabilize Regulatory T Cells.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
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Authors and funding
15 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundAlthough hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells.
methodsThis study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice.
resultsLipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid, accumulated in the lymphatic environment. Lysophosphatidic acid enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering Th1/Th2 (T helper type1/2) subsets. This occurs via the proteolytic degradation of MEKK1 (mitogen-activated protein kinase kinase kinase 1) and the subsequent inhibition of TGF (transforming growth factor)-β1 production in LECs. Targeting calpain systems in LECs expanded Tregs in the blood circulation and reduced aortic atherosclerosis in hypercholesterolemic mice, concomitant with the reduction of proinflammatory macrophages in the lesions. Treg expansion in the blood circulation and atheroprotection in calpain-targeted mice was prevented by the administration of TGF-β type-I receptor inhibitor. Moreover, lysophosphatidic acid-induced calpain overactivation potentiated the IL (interleukin)-18/NF-κB (nuclear factor κB)/VCAM1 (vascular cell adhesion molecule 1) axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Indeed, VCAM1 in LECs was upregulated in hypercholesterolemic mice and human cases of coronary artery disease. Neutralization of VCAM1 or targeting LEC calpain systems recovered afferent Treg transportation via lymphatic vessels in mice.
conclusionsCalpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.