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Inhibition or deletion of 11Β-HSD1 does not increase angiogenesis in ischemic retinopathy

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  • Diabetes and Metabolism_revised Callam Davidson 121216

    Rights statement: ACKNOWLEDGEMENTS Dr Scott Webster (CVS, QMRI, Edinburgh) provided 11β-HSD1 antibody. Claire L Kitson (CEM, QUB, Belfast) assisted in obtaining and analysing samples. FUNDING We acknowledge the support of the British Heart Foundation Centre of Research Excellence. DUALITY OF INTEREST BRW and PWFH are inventors on relevant patents owned by the University of Edinburgh. BRW has consulted extensively with pharmaceutical companies developing 11-HSD1 inhibitors and is Principal Investigator for a programme developing novel 11-HSD1 inhibitors, funded by the Wellcome Trust and recently licenced to Actinogen Medical. CONTRIBUTION STATEMENT Brian R Walker is guarantor of the article. ARD, CTD, PWFH, AWS and BRW designed the studies, analysed data and wrote or edited the manuscript. CMMcV, JVG, CTD and RM obtained and analysed samples and data and reviewed the manuscript.

    Accepted author manuscript, 31.5 KB, Word document

    Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Original languageEnglish
JournalDiabetes and Metabolism
DOIs
Publication statusPublished - 11 Jan 2017

Abstract

11-Hydroxysteroid dehydrogenase type I (11-HSD1) regenerates active glucocorticoids (cortisol in humans, corticosterone in rodents) from inert 11-keto metabolites [1]. Selective 11-HSD1 inhibitors have been shown to be safe and effective in the treatment of type 2 diabetes [2], lowering intracellular glucocorticoid concentrations in liver and adipose tissue (and thereby enhancing insulin sensitivity) [3]. They also improve a number of features of the metabolic syndrome, including liver fat content [4], are potentially atheroprotective [5] and improve cognition [6]. Although no longer under development for blood glucose lowering alone, 11-HSD1 inhibitors are being re-profiled for additional indications and may yet be prescribed in patients with type 2 diabetes.
11-HSD1 is also expressed in smooth muscle cells throughout the vasculature [7]. By acting directly through glucocorticoid receptors in the blood vessel wall, glucocorticoids tonically inhibit angiogenesis [8]. Loss of 11-HSD1, and the resulting reduction of glucocorticoid action in blood vessels, is associated with enhanced angiogenesis in multiple sites and has been shown to be beneficial in the myocardium after coronary artery occlusion and in skin following wound incision [9].
Angiogenesis can also contribute to pathology, as seen in solid tumour development and ischemic retinopathies such as retinal vein occlusions and proliferative diabetic retinopathy (PDR). If 11-HSD1 inhibitors are to be used for chronic treatment in patients with type II diabetes, then there is a concern that they may accelerate the progression of inappropriate blood vessel growth in the retina and exacerbate progression to sight-threatening PDR.
This study tests the hypothesis that pharmacological inhibition or deletion of 11-HSD1 promotes pathological retinal neovascularisation. Retinal vascular remodelling was induced using the oxygen induced retinopathy (OIR) model [10] in which exposure of neonatal mice to hyperoxia from postnatal days 7 to 12 causes obliteration and cessation of development of central retinal capillary beds so that, on return to normoxia, a potent pre-retinal neovascular response is induced. Expression and localisation of 11β-HSD1 in the retina was also investigated by immunohistochemistry.

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