Low-density lipoprotein (LDL) accumulation in the arterial wall contributes to atherosclerosis initiation and progression. Activin A receptor-like type 1 (ACVRL1, called activin-like kinase receptor (ALK1)) is a recently identified receptor that mediates LDL entry and transcytosis in endothelial cells (ECs). However, the role of this pathway in vivo is not yet known. In the present study, we show that genetic deletion of ALK1 in arterial ECs of mice substantially limits LDL accumulation, macrophage infiltration and atherosclerosis without affecting cholesterol or triglyceride levels. Moreover, a selective monoclonal antibody binding ALK1 efficiently blocked LDL transcytosis, but not bone morphogenetic protein-9 (BMP9) signaling, dramatically reducing plaque formation in LDL receptor knockout mice fed a high-fat diet. Thus, our results demonstrate that blocking LDL transcytosis into the endothelium may be a promising therapeutic strategy that targets the initiating event of atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1038/s44161-023-00266-2 | DOI Listing |
Transl Res
December 2024
Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology. Wuhan 430077, China. Electronic address:
Arterioscler Thromb Vasc Biol
September 2024
Keenan Centre for Biomedical Research, St. Michael's Hospital, Toronto, ON, Canada (E.J., T.W.W.H., C.W., W.L.L.).
Background: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1β (interleukin-1β); this significantly reduced cardiovascular events. However, whether IL-1β regulates early disease, particularly LDL transcytosis, remains unknown.
View Article and Find Full Text PDFCirc Res
July 2024
Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, UW Medicine Diabetes Institute (V.K., Y.H., F.K., M.S.-A., J.E.K., B.S., J.W.H., T.V., K.E.B.).
Background: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies.
View Article and Find Full Text PDFJ Atheroscler Thromb
June 2024
Division of Endocrinology, New York University Grossman School of Medicine.
Atherosclerosis begins with the infiltration of cholesterol-containing lipoproteins into the arterial wall. White blood cell (WBC)-associated inflammation follows. Despite decades of research using genetic and pharmacologic methods to alter WBC function, in humans, the most effective method to prevent the initiation and progression of disease remains low-density lipoprotein (LDL) reduction.
View Article and Find Full Text PDFJ Lipid Res
April 2024
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; Keenan Research Centre, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address:
Atherosclerosis results from the deposition and oxidation of LDL and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either scavenger receptor B1 (SR-B1) or activin A receptor-like kinase 1 on the apical side of endothelial cells leading to its transit and release on the basolateral side.
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