Role of shear stress-induced red blood cell released ATP in atherosclerosis.

IF 4.1 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Yunpei Zhang, Haoyu Sun, Aayush Gandhi, Yong Du, Saman Ebrahimi, Yanyan Jiang, Sulei Xu, Hope Uwase, Alane Seidel, Sarah S Bingaman, Amy C Arnold, Christian Nguyen, Wei Ding, Matthew D Woolard, Ryan Hobbs, Prosenjit Bagchi, Pingnian He
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引用次数: 0

Abstract

Altered hemodynamics is a key factor for atherosclerosis. For decades, endothelial cell (EC) responses to fluid-generated wall shear stress have been the central focus for atherogenesis. However, circulating blood is not a cell-free fluid, it contains mechanosensitive red blood cells (RBCs) that are also subjected to altered hemodynamics and release a large amount of ATP, but their impact on atherosclerosis has been overlooked. The focus of this study is the role of shear stress (SS)-induced RBC-released ATP in atherosclerosis. Hypercholesterolemic mouse models with and without RBC-Pannexin 1 deletion were used for the study. Results showed that SS-induced release of ATP from RBCs was at µM concentrations, three-orders of magnitude higher than that from other cell types. Suppression of RBC-released ATP via deletion of Pannexin 1, a mechanosensitive ATP-permeable channel, reduced high-fat diet-induced aortic plaque burden by 40%-60%. Importantly, the location and the extent of aortic atherosclerotic lesions spatially matched with the ATP deposition profile at aortic wall predicted by a computational fluid dynamic (CFD) model. Furthermore, hypercholesterolemia increases EC susceptibility to ATP with potentiated increase in [Ca2+]i, an initial signaling for aortic EC barrier dysfunction, and an essential cause for lipid accumulation and inflammatory cell infiltration. The computational prediction also provides a physics-based explanation for RBC-released ATP-induced sex disparities in atherosclerosis. Our study reveals an important role of RBC-released ATP in the initiation and progression of atherosclerosis. These novel findings provide a more comprehensive view of how altered hemodynamics and systemic risk factors synergistically contribute to atherosclerosis.NEW & NOTEWORTHY This study reveals that, in addition to fluid-derived wall shear stress, the disturbed blood flow-induced release of ATP from mechanosensitive red blood cells (RBCs), the major cellular components of blood, along with hypercholesterolemia-induced increases in endothelial cell susceptibility to ATP contribute significantly to the initiation and progression of atherosclerosis. These novel findings advance our current understanding of how altered hemodynamics and hypercholesterolemia synergistically contribute to atherosclerosis for the first time with the inclusion of RBCs.

剪切应力诱导红细胞释放ATP在动脉粥样硬化中的作用。
血液动力学改变是动脉粥样硬化的关键因素。几十年来,内皮细胞(EC)对流体产生的壁剪切应力的反应一直是动脉粥样硬化的中心焦点。然而,循环血液不是无细胞的液体,它含有机械敏感的红细胞(rbc),这些红细胞也会受到血流动力学的改变并释放大量的ATP,但它们对动脉粥样硬化的影响一直被忽视。本研究的重点是剪切应力(SS)诱导的红细胞释放ATP在动脉粥样硬化中的作用。高胆固醇血症小鼠模型有或没有RBC-Pannexin 1缺失被用于研究。结果表明,ss诱导红细胞释放的ATP达到μM浓度,比其他细胞高3个数量级。通过删除Pannexin 1(一种机械敏感的ATP渗透通道)抑制红细胞释放的ATP,可减少40-60%高脂饮食引起的主动脉斑块负担。重要的是,主动脉粥样硬化病变的位置和范围在空间上与计算流体动力学(CFD)模型预测的主动脉壁ATP沉积分布相匹配。此外,高胆固醇血症增加EC对ATP的易感性,并增强[Ca2+]i的增加,这是主动脉EC屏障功能障碍的初始信号,也是脂质积累和炎症细胞浸润的重要原因。计算预测也为动脉粥样硬化中红细胞释放的atp诱导的性别差异提供了基于物理的解释。我们的研究揭示了红细胞释放的ATP在动脉粥样硬化的发生和发展中的重要作用。这些新发现为血液动力学改变和全身危险因素如何协同促进动脉粥样硬化提供了更全面的观点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.60
自引率
10.40%
发文量
202
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology-Heart and Circulatory Physiology publishes original investigations, reviews and perspectives on the physiology of the heart, vasculature, and lymphatics. These articles include experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact and integrative animal and organ function to the cellular, subcellular, and molecular levels. The journal embraces new descriptions of these functions and their control systems, as well as their basis in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new mechanistic physiological insights that determine the performance of the normal and abnormal heart and circulation.
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