AQP1 differentially orchestrates endothelial cell senescence

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Biology Pub Date : 2024-08-22 DOI:10.1016/j.redox.2024.103317
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Abstract

Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1's differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases.

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AQP1 以不同方式协调内皮细胞的衰老
随着年龄的增长,衰老内皮细胞(EC)的积累是导致心血管疾病的关键因素。然而,人们对调节内皮细胞衰老的机制和信号通路知之甚少。在本报告中,我们描述了以前未认识到的水通道蛋白 1(AQP1)在协调细胞外过氧化氢(HO)诱导的主动脉 EC 细胞衰老中的作用。我们的研究结果强调了AQP1对衰老标志的不同影响,包括细胞周期停滞、衰老相关分泌表型(SASP)和DNA损伤反应,并错综复杂地调节血管生成。在增殖的血管内皮细胞中,AQP1 对维持血管生成能力至关重要,而 AQP1 的破坏会诱发形态学和线粒体的改变,最终导致衰老和血管生成受损。相反,在衰老的心血管细胞中敲除或选择性阻断 AQP1 可挽救过量 HO 诱导的细胞衰老表型和代谢功能障碍,从而改善内在的血管生成无能。从机理上讲,AQP1 可促进 HO 跨膜转运,加剧氧化剂敏感激酶 CaMKII-AMPK 的作用。这一过程抑制了 HDAC4 的转位,从而抑制了增殖 EC 中 Mef2A-eNOS 信号的传递。然而,在衰老的心血管细胞中,AQP1 的过表达与 HDAC4-Mef2A 复合物的保留和 eNOS 信号的下调有关。总之,我们的研究发现 AQP1 是 HDAC4-Mef2A 依赖性心血管细胞衰老和血管生成潜能的新型表观遗传调节因子,突出了其作为治疗靶点以对抗与年龄相关的心血管疾病的潜力。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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