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Pharmacol Ther. 2018 Mar;183:22-33. doi: 10.1016/j.pharmthera.2017.09.003. Epub 2017 Sep 20.

Hypoxia inducible factor as a therapeutic target for atherosclerosis.

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Cardiovascular Division, King's College London BHF Centre, London, UK.
Cardiovascular Division, King's College London BHF Centre, London, UK. Electronic address:
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing, China. Electronic address:


Atherosclerosis is a highly prevalent disease that can significantly increase the risk of major vascular events, such as myocardial or cerebral infarctions. The anoxemia theory states that a disparity between oxygen supply and demand contributes to atherosclerosis. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein, part of the basic helix-loop-helix family and one of the main regulators of cellular responses in a low‑oxygen environment. It plays a key role in the development of atherosclerosis through cell-specific responses, acting on endothelial cells, vascular smooth muscle cells (SMCs) and macrophages. Through the upregulation of VEGF, NO, ROS and PDGF, HIF-1 is able to cause endothelial cell dysfunction, proliferation, angiogenesis and inflammation. Activation of the NF-kB pathway in endothelial cells is an important contributor to inflammation and positively feedbacks to HIF-1. HIF-1 also plays a significant role in both the proliferation and migration of smooth muscle cells - two important features of atherosclerosis, while the formation of foam cells (lipid-laden macrophages) is also a critical step in atherosclerosis and mediated by HIF-1 through various mechanisms such as dysfunctional efflux pathways in macrophages. Overall, HIF-1 exerts its effect on the pathogenesis of atherosclerosis via a variety of molecular and cellular events in the process. In this review article, we examine the effects HIF-1 on vascular cells and macrophages in the development of atherosclerosis, highlighting the environmental cues and signalling pathways that control HIF-1 expression/activation within the vasculature. We will highlight the potential of HIF-1 as a therapeutic target on the disease development.


Atherosclerosis; Endothelial cells; HIF; Macrophages; Smooth muscle cells

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