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.

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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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