内皮 YAP/TAZ 激活促进 Hutchinson-Gilford progeria 综合征小鼠模型的动脉粥样硬化。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-01 DOI:10.1172/JCI173448
Ana Barettino, Cristina González-Gómez, Pilar Gonzalo, María J Andrés-Manzano, Carlos R Guerrero, Francisco M Espinosa, Rosa M Carmona, Yaazan Blanco, Beatriz Dorado, Carlos Torroja, Fátima Sánchez-Cabo, Ana Quintas, Alberto Benguría, Ana Dopazo, Ricardo García, Ignacio Benedicto, Vicente Andrés
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引用次数: 0

摘要

哈钦森-吉尔福德早衰综合征(HGPS)是一种极其罕见的疾病,由早衰素表达引起,早衰素是一种由 LMNA 基因点突变产生的异常蛋白质。HGPS 患者衰老加速,主要死于动脉粥样硬化并发症,如心肌梗塞、心力衰竭或中风。然而,HGPS血管病理学的基本机制仍不明确。我们使用单细胞 RNA 测序技术分析了表达 LmnaG609G/G609G 的小鼠和野生型对照组的主动脉特征,重点研究了内皮细胞(ECs)。HGPS ECs的基因表达变化与细胞外基质改变、白细胞外渗增加以及具有PDZ结合域的YAP/TAZ转录激活因子机械传感途径的激活有关,所有这些变化都通过不同的技术进行了验证。原子力显微镜实验表明,原发性主动脉内皮下细胞外基质较硬,对活体HGPS小鼠的超声波评估显示主动脉血流紊乱,这两种情况都是诱导EC中YAP/TAZ通路的关键因素。用verteporfin抑制YAP/TAZ可减少主动脉内膜层的白细胞积聚,减轻类早衰小鼠的动脉粥样硬化负担。我们的研究结果表明,内皮YAP/TAZ信号传导是HGPS血管疾病的一个关键机制,并为开发YAP/TAZ靶向药物以改善早老素诱导的动脉粥样硬化开辟了一条新途径。
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Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortas, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ targeting drugs to ameliorate progerin-induced atherosclerosis.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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