Apolipoprotein E Deficiency Causes Endothelial Dysfunction in the Mouse Retina.

Jenia Kouchek Zadeh,Andreas Daiber,Panagiotis Laspas,Mayagozel B Zhutdieva,Can Yuksel,Christoph Brochhausen,Huige Li,Norbert Pfeiffer,Aytan Musayeva,Matthias Oelze,Adrian Gericke,Ning Xia

doi:10.1155/2019/5181429

Abstract

Objective Atherogenic lipoproteins may impair vascular reactivity consecutively causing tissue damage in multiple organs via abnormal perfusion and excessive reactive oxygen species generation. We tested the hypothesis that chronic hypercholesterolemia causes endothelial dysfunction and cell loss in the retina. Methods Twelve-month-old apolipoprotein E-deficient (ApoE-/-) mice and age-matched wild-type controls were used in this study (n = 8 per genotype for each experiment). Intraocular pressure, blood pressure, and ocular perfusion pressure were determined. Retinal arteriole responses were studied in vitro, and reactive oxygen and nitrogen species were quantified in the retinal and optic nerve cryosections. The expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the NADPH oxidase isoforms, NOX1, NOX2, and NOX4, were determined in retinal cryosections by immunofluorescence microscopy. Pro- and antioxidant redox genes were quantified in retinal explants by PCR. Moreover, cell number in the retinal ganglion cell layer and axon number in the optic nerve was calculated. Results Responses to the endothelium-dependent vasodilator, acetylcholine, were markedly impaired in retinal arterioles of ApoE-/- mice (P < 0.01). LOX-1 (P = 0.0007) and NOX2 (P = 0.0027) expressions as well as levels of reactive oxygen species (P = 0.0022) were increased in blood vessels but not in other retinal structures. In contrast, reactive nitrogen species were barely detectable in both mouse genotypes. Messenger RNA for HIF-1α, VEGF-A, NOX1, and NOX2, but also for various antioxidant redox genes was elevated in the retina of ApoE-/- mice. Total cell number in the retinal ganglion cell layer did not differ between ApoE-/- and wild-type mice (P = 0.2171). Also, axon number in the optic nerve did not differ between ApoE-/- and wild-type mice (P = 0.6435). Conclusion Apolipoprotein E deficiency induces oxidative stress and endothelial dysfunction in retinal arterioles, which may trigger hypoxia in the retinal tissue. Oxidative stress in nonvascular retinal tissue appears to be prevented by the upregulation of antioxidant redox enzymes, resulting in neuron preservation.

Highlights

Hypercholesterolemia is a main risk factor for atherosclerosis and a primary cause of cardiovascular organ dysfunction [1,2,3]
The findings of the present study suggest that lipoprotein receptor-1 (LOX-1), NOX2, and reactive oxygen species (ROS) are involved in mediating hypercholesterolemia-induced endothelial dysfunction in the retina, which is in concert with a study in cerebral blood vessels reporting that NOX2-derived ROS abrogated nitric oxide function in ApoE-/- mice [40]
Our study demonstrates that chronic apolipoprotein E deficiency promotes endothelial dysfunction in retinal arterioles

Summary

Introduction

Hypercholesterolemia is a main risk factor for atherosclerosis and a primary cause of cardiovascular organ dysfunction [1,2,3]. A recent meta-analysis reported on an association between hyperlipidemia and an increased risk of glaucoma [12], which is one of the leading causes of vision impairment worldwide characterized by progressive loss of retinal ganglion cells (RGCs), visual field defects, and specific morphological changes of the optic nerve [13,14,15]. Hypercholesterolemia might be linked to glaucoma via inducing vascular endothelial dysfunction in the eye Despite these findings, the specific effects of hypercholesterolemia on retinal vascular function are unknown at the molecular level. The specific effects of hypercholesterolemia on retinal vascular function are unknown at the molecular level It remains to be established whether chronic hypercholesterolemia has an influence on RGC viability. We used apolipoprotein E-deficient mice (ApoE-/-) for our studies, because they develop spontaneous severe hypercholesterolemia and atherosclerotic lesions in various blood vessels similar to those found in humans [18,19,20]

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Discussion

Conclusion