In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.
Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8–10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.
Background Development of atherosclerosis depends on the interaction between various factors. Type 2 diabetes accelerates these interactions and predisposes to rapid progression of atherosclerosis. Diminution of vasoprotective effects of perivascular adipose tissue (PVAT) in metabolic disorders suggests a molecular link between diabetes and atherosclerosis. Objectives To assess the paracrine role of the PVAT on the progression of diabetic atherosclerosis, via intercellular communications between PVAT and the underlying vasculature. Methods Periaortic adipose tissue from Type 2 diabetic (db/db) mice were transplanted around the right common carotid arteries of ApoE‐/‐ mice, followed by 16 weeks of atherogenic diet. Carotid arteries and adipose tissues were assessed for lesion formation and inflammatory markers, respectively. Adipose stem cells (ASCs) from PVAT were treated with lipopolysaccharide (1µg/ml), palmitate (200µM), and high‐glucose (42 mM) for 24 hrs (denoted as P‐ASCs) to mimic type 2 diabetes‐associated metabolic alterations. Small extracellular vesicles (sEV) were isolated from the conditioned media. Aortic vascular smooth muscle cells (SMCs) were incubated with ASC‐derived sEV (25µg/ml). The migratory potential of SMCs was evaluated by wound healing assay. Results Histological analysis displayed accelerated atherogenic plaque formation with transplantation of type 2 diabetic PVAT around the carotid arteries of ApoE‐/‐ mice, which is otherwise resistant to plaque formation. Pro‐inflammatory markers were significantly increased in periaortic adipose tissue from db/db compared to WT. sEV secreted from P‐ASCs greatly enhanced the SMC migration when compared with the control ASCs. Conclusions Our data shows type 2 diabetes‐accelerated progression of atherosclerosis is mediated by PVAT‐derived sEV.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.