Endothelial-to-Mesenchymal Transition Contributes to Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome

作者：Magda R. Hamczyk, Rosa M. Nevado, Pilar Gonzalo, María J. Andrés‐Manzano, Paula Nogales, Vı́ctor Quesada, Aranzazú Rosado, Carlos Torroja, Fátima Sánchez‐Cabo, Ana Dopazo, Jacob Fog Bentzon, Carlos López-Otı́n, Vicente Andrés · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.065768 · 被引用次数：36 · 研究领域：Nuclear Structure and Function、Cellular transport and secretion、Clusterin in disease pathology

BACKGROUND: -deficient mice. However, the impact of progerin-driven VSMC defects on endothelial cells (ECs) remained unclear. METHODS: -deficient C57BL/6J mice with ubiquitous, VSMC-, EC- or myeloid-specific progerin expression fed a normal or high-fat diet were used to study endothelial phenotype during Hutchinson-Gilford progeria syndrome-associated atherosclerosis. Endothelial permeability to low-density lipoproteins was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein and confocal microscopy analysis of the aorta. Leukocyte recruitment to the aortic wall was evaluated by en face immunofluorescence. Endothelial-to-mesenchymal transition (EndMT) was assessed by quantitative polymerase chain reaction and RNA sequencing in the aortic intima and by immunofluorescence in aortic root sections. TGFβ (transforming growth factor β) signaling was analyzed by multiplex immunoassay in serum, by Western blot in the aorta, and by immunofluorescence in aortic root sections. The therapeutic benefit of TGFβ1/SMAD3 pathway inhibition was evaluated in mice by intraperitoneal injection of SIS3 (specific inhibitor of SMAD3), and vascular phenotype was assessed by Oil Red O staining, histology, and immunofluorescence in the aorta and the aortic root. RESULTS: -null mice provoked alterations in aortic ECs, including increased permeability to low-density lipoprotein and leukocyte recruitment. Atherosclerotic lesions in these progeroid mouse models, but not ...