Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation

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Abstract

Objective:

The calcineurin-NFAT (nuclear factor for activated T cells)-DSCR (Down syndrome critical region)-1 pathway plays a crucial role as the downstream effector of VEGF (vascular endothelial growth factor)-mediated tumor angiogenesis in endothelial cells. A role for DSCR-1 in different organ microenvironment such as the cornea and its role in ocular diseases is not well understood. Corneal changes can be indicators of various disease states and are easily detected through ocular examinations.

Approach and Results:

The presentation of a corneal arcus or a corneal opacity due to lipid deposition in the cornea often indicates hyperlipidemia and in most cases, hypercholesterolemia. Although the loss of Apo (apolipoprotein) E has been well characterized and is known to lead to elevated serum cholesterol levels, there are few corneal changes observed in ApoE ^−/− mice. In this study, we show that the combined loss of ApoE and DSCR-1 leads to a dramatic increase in serum cholesterol levels and severe corneal opacity with complete penetrance. The cornea is normally maintained in an avascular state; however, loss of Dscr-1 is sufficient to induce hyper-inflammatory and -oxidative condition, increased corneal neovascularization, and lymphangiogenesis. Furthermore, immunohistological analysis and genome-wide screening revealed that loss of Dscr-1 in mice triggers increased immune cell infiltration and upregulation of SDF (stromal derived factor)-1 and its receptor, CXCR4 (C-X-C motif chemokine ligand receptor-4), potentiating this signaling axis in the cornea, thereby contributing to pathological corneal angiogenesis and opacity.

Conclusions:

This study is the first demonstration of the critical role for the endogenous inhibitor of calcineurin, DSCR-1, and pathological corneal angiogenesis in hypercholesterolemia induced corneal opacity.

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Most cited references 36

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Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.

William C. Aird (2007)

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the second of a 2-part review on the phenotypic heterogeneity of blood vessel endothelial cells. The first part discusses the scope, the underlying mechanisms, and the diagnostic and therapeutic implications of phenotypic heterogeneity. Here, these principles are applied to an understanding of organ-specific phenotypes in representative vascular beds including arteries and veins, heart, lung, liver, and kidney. The goal is to underscore the importance of site-specific properties of the endothelium in mediating homeostasis and focal vascular pathology, while at the same time emphasizing the value of approaching the endothelium as an integrated system.

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Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.

William C. Aird (2007)

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium.

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Down syndrome suppression of tumor growth and the role of the calcineurin inhibitor DSCR1

Kwan-Hyuck Baek, Alexander Zaslavsky, Ryan Lynch … (2009)

The incidence of many cancer types is significantly reduced in individuals with Down syndrome1–4 and it is proposed that this broad cancer protection is conferred by the elevated expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is the Down syndrome candidate region-1 (Dscr1, RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling via the calcineurin pathway5–10. Here we show that DSCR1 is elevated in Down syndrome individuals and a mouse model of Down syndrome. Further, we show that the modest elevation in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumor growth in mice and that such resistance is a consequence of a deficit in tumor angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1 together with another chromosome 21 gene DYRK1A, may be sufficient to dramatically diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down syndrome and identifies the calcineurin signalling pathway and its regulators DSCR1 and DYRK1A as potential therapeutic targets in cancers arising in all individuals.