Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice.
Nat Cardiovasc Res
; 2(5): 438-448, 2023 May.
Article
em En
| MEDLINE
| ID: mdl-39196046
ABSTRACT
Low-density lipoprotein (LDL) accumulation in the arterial wall contributes to atherosclerosis initiation and progression1. 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)2,3. 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de LDL
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Receptores de Activinas Tipo II
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Células Endoteliais
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Aterosclerose
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Transcitose
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Lipoproteínas LDL
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article