血管生成素-2 可逆转早衰症血管中的内皮细胞功能障碍。

IF 8 1区 医学 Q1 CELL BIOLOGY
Aging Cell Pub Date : 2024-10-18 DOI:10.1111/acel.14375
Sahar Vakili, Elizabeth K Izydore, Leonhard Losert, Wayne A Cabral, Urraca L Tavarez, Kevin Shores, Huijing Xue, Michael R Erdos, George A Truskey, Francis S Collins, Kan Cao
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引用次数: 0

摘要

哈钦森-吉尔福德早衰综合征(HGPS)是一种罕见的儿童早衰症,是由于层粘连蛋白 A 基因的点突变导致层粘连蛋白 A 的一种有毒形式--早老素。动脉粥样硬化加速导致心脏病发作和中风是这些患者的主要死因。内皮细胞(EC)功能障碍是与 HGPS 相关的心血管疾病(CVD)的发病机制之一。内皮细胞与细胞之间的通讯在血管的发育过程中非常重要,如果通讯中断,就会导致心血管病变。然而,目前还不清楚早老素是如何干扰这种沟通并导致血管功能障碍的。通过对健康和HGPS患者的EC分泌物进行抗体阵列筛选,发现血管生成素-2(Ang2)是HGPS EC中一个下调的信号分子。在 HGPS 小鼠模型的主动脉中也发现了类似的 Ang2 mRNA 和蛋白下调现象。向 HGPS ECs 中添加 Ang2 可挽救血管生成,使内皮细胞迁移和基因表达正常化,并通过激活 eNOS 恢复一氧化氮的生物利用率。此外,Ang2 的添加还能逆转 HGPS ECs 对血管平滑肌细胞的不利旁分泌效应。最后,通过使用腺嘌呤碱编辑器(ABE)校正的 HGPS ECs 和表达早老素的 HUVECs,我们证明了早老素和 Ang2 表达之间的负相关。最后,我们的研究结果表明,Ang2 通过与 Tie2 受体结合,激活 Akt 介导的通路,在心血管细胞中发挥有益作用。这些结果从分子角度揭示了 HGPS 中心血管细胞的功能障碍,并表明 Ang2 治疗对 HGPS 相关心血管疾病具有潜在的治疗作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD.

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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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