Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

Abstract

Aims/hypothesis The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. Methods Endothelial cells were grown in normal-and highglucose (5 and 25 mmol/l) media with and without UII (10 −8 mol/l) and/or the UII receptor antagonist, SB-657510 (10 −8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mgkg −1 day −1 ; n=20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. Results In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. Conclusions/interpretation This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…Consistent with the widespread distribution of UT, it has been shown that UII exerts a number of biologic effects including regulation of behaviors and neuroendocrine activities, as well as central and peripheral control of blood pressure and heart rate Vaudry et al, 2010). Clinical studies have provided evidence that UII and UT are implicated in various pathologies, including cardiovascular diseases Ng et al, 2002;Richards et al, 2002;You et al, 2012;Watson et al, 2013), renal diseases , and diabetes (Wenyi et al, 2003;Sidharta et al, 2009). The various activities of UII and the potential implication of the urotensinergic system in various pathologies have prompted academic laboratories and pharmaceutical companies to design specific agonists and antagonists that are currently used for basic research and may lead to therapeutic applications Maryanoff and Kinney, 2010;Tsoukas et al, 2011;Merlino et al, 2013).…”

“…A recent study by You et al (2012) demonstrates that UII gene deletion in atherosclerotic mice, as well as the use of the UT antagonist SB657510, ameliorates many features of atherosclerosis, including reducing serum cytokines and adipokines, improving aortic atherosclerosis, reducing weight gain and fat deposition, decreasing blood pressure, and improving glucose tolerance. After observing increased UII expression in diabetes-associated atherosclerotic mice and humans, Watson et al (2013) demonstrated that the same UT antagonist, SB657510, attenuated diabetes-associated plaque development. Interestingly, Bousette et al (2009) observed that genetic deletion of UT on ApoE knockout mice (a model for atherosclerosis) increased atherosclerosis as well as serum insulin and lipids in these mice.…”

Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

“…Immunohistochemical stains were performed on paraffin sections (4 μm) of aorta and kidney for nitrotyrosine, a marker of oxidative stress (rabbit polyclonal; Millipore, Billerica, MA, USA; 1:100), fibronectin, a marker of fibrosis (rabbit polyclonal; Abcam, Cambridge, AM USA; 1:200) and F4/80, a marker of macrophages (rat monoclonal; Abcam, Cambridge, AM, USA; 1:100) as previously described, and analysed in a blinded fashion [5,26,27].…”

Urotensin II Inhibits Skeletal Muscle Glucose Transport Signaling Pathways via the NADPH Oxidase Pathway

“…Importantly, UII and UT are abundant in the skeletal muscle of mouse and monkey, and radio-ligand binding assay has shown that UT binds [ 125 I]UII with high affinity in skeletal muscle [5]. Besides its important role in the cardiovascular system, UII also participates in metabolic regulation and plays a significant role in diabetes and its complications [6,7]. Our previous studies demonstrated that the UII/UT system is up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM), and UII inhibited insulin-stimulated 2-DG uptake in skeletal muscle [8].…”