Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells.

Autor: Myers CG; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Viswambharan H; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Haywood NJ; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Bridge K; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Turvey S; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Armstrong T; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Lunn L; Department of Chemistry University of Leeds, Leeds, United Kingdom., Meakin PJ; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Porter KE; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Clavane EM; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., Beech DJ; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom; National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, United Kingdom., Cubbon RM; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom; National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, United Kingdom., Wheatcroft SB; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom., McPhillie MJ; Department of Chemistry University of Leeds, Leeds, United Kingdom., Issad T; Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014, Paris, France., Fishwick CW; Department of Chemistry University of Leeds, Leeds, United Kingdom., Kearney MT; Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom; National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds, United Kingdom. Electronic address: m.t.kearney@leeds.ac.uk., Simmons KJ; School of Biomedical Sciences, Faculty of Biological Sciences & Astbury Centre, University of Leeds, United Kingdom.
Jazyk: angličtina
Zdroj: Molecular and cellular endocrinology [Mol Cell Endocrinol] 2024 Dec 01; Vol. 594, pp. 112387. Date of Electronic Publication: 2024 Oct 16.
DOI: 10.1016/j.mce.2024.112387
Abstrakt: Objectives: The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells.
Methods: We performed a high-throughput small molecule screening, based on a homology model of the apo hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation.
Results: Our studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effects on IR or IGF-1R. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus.
Conclusions: We identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptors leads to an increase in insulin-induced serine phosphorylation of the critical downstream signalling kinase, Akt. The underpinning mechanism appears, at least in part to involve the attenuation of the inhibitory effect of IR: IGF-1R hybrid receptors on PI3-kinase signalling.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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