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 Lmna^G609G/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 aortae, 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.

中文翻译：

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内皮 YAP/TAZ 激活促进 Hutchinson-Gilford 早衰综合症小鼠模型中的动脉粥样硬化


Hutchinson-Gilford早衰综合症（HGPS）是一种由早衰素表达引起的极其罕见的疾病，早衰素是由LMNA基因中的点突变产生的异常蛋白。HGPS 患者表现出加速衰老并过早死亡，主要死于动脉粥样硬化并发症，例如心肌梗塞、心力衰竭或中风。然而，HGPS 血管病理学的潜在机制仍然不清楚。我们使用单细胞 RNA 测序来表征表达早老蛋白的 Lmna^G609G/G609G 小鼠和野生型对照的主动脉，特别关注内皮细胞 （EC）。HGPS ECs 显示与细胞外基质改变、白细胞外渗增加以及 yes 相关蛋白 1/转录激活因子与 PDZ 结合域 （YAP/TAZ） 机械感应通路的激活相关的基因表达变化，所有这些都通过不同的技术得到验证。原子力显微镜实验表明，早衰样主动脉中内皮下细胞外基质较硬，活 HGPS 小鼠的超声评估显示主动脉血流紊乱，这两者都是 ECs 中 YAP/TAZ 通路的关键诱导剂。维替泊芬抑制 YAP/TAZ 减少了主动脉内膜层白细胞的积累，并减少了早衰小鼠的动脉粥样硬化负荷。我们的研究结果确定内皮 YAP/TAZ 信号传导是 HGPS 血管疾病的关键机制，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。