Upregulation of Neogenin-1 by a CREB1-BAF47 Complex in Vascular Endothelial Cells is Implicated in Atherogenesis.

Nan Li,Xiaocen Kong,Yujia Xue,Junliang Chen,Yuanyuan Zhang,Hong Liu

doi:10.3389/fcell.2022.803029

Abstract

Atherosclerosis is generally considered a human pathology of chronic inflammation, to which endothelial dysfunction plays an important role. Here we investigated the role of neogenin 1 (Neo-1) in oxidized low-density lipoprotein (oxLDL) induced endothelial dysfunction focusing on its transcriptional regulation. We report that Neo-1 expression was upregulated by oxLDL in both immortalized vascular endothelial cells and primary aortic endothelial cells. Neo-1 knockdown attenuated whereas Neo-1 over-expression enhanced oxLDL-induced leukocyte adhesion to endothelial cells. Neo-1 regulated endothelial-leukocyte interaction by modulating nuclear factor kappa B (NF-κB) activity to alter the expression of adhesion molecules. Neo-1 blockade with a blocking antibody ameliorated atherogenesis in Apoe −/− mice fed a Western diet. Ingenuity pathway analysis combined with validation assays confirmed that cAMP response element binding protein 1 (CREB1) and Brg1-associated factor 47 (BAF47) mediated oxLDL induced Neo-1 upregulation. CREB1 interacted with BAF47 and recruited BAF47 to the proximal Neo-1 promoter leading to Neo-1 trans-activation. In conclusion, our data delineate a novel transcriptional mechanism underlying Neo-1 activation in vascular endothelial cells that might contribute to endothelial dysfunction and atherosclerosis.

Highlights

Coronary heart disease represents one of the major causes for heart failure, which affects ~30 million patients annually and is the leading cause of deaths worldwide (Savarese and Lund, 2017)
In order to determine the effect of pro-atherosclerotic stimuli on neogenin 1 (Neo-1) expression, immortalized human vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAECs) were treated with different doses of oxidized low-density lipoprotein
The possibility that Neo-1 upregulation by oxidized low-density lipoprotein (oxLDL) in vascular smooth muscle cells (VSMCs) or macrophages may contribute to atherogenesis and offer explanation to the observed phenotype cannot be ruled out

Summary

Introduction

Coronary heart disease represents one of the major causes for heart failure, which affects ~30 million patients annually and is the leading cause of deaths worldwide (Savarese and Lund, 2017). Atherosclerosis is characterized by the deposition of fat-laden plaques in the arteries causing progressive narrowing of the blood vessel and subsequently coronary heart disease (Libby, 2021a). Decades of research have led to the consensus that atherosclerosis is a human pathology of chronic vascular inflammation (Libby, 2021b). On the other hand, modulating the inflammatory response in the vessels has been shown to alter the development and progression of atherosclerosis in model animals (Libby et al, 2013). The most convincing piece of evidence to support the long-held view that vascular inflammation is the linchpin of atherogenesis comes from a recently published clinic study that shows the efficacy of a monoclonal antibody targeting the pro-inflammatory cytokine IL-1β (Canakinumab) in the treatment of atherosclerosis (Ridker et al, 2017)

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