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Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism

Item Type:Article
Title:Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism
Creators Name:Gu, M. and Mordwinkin, N.M. and Kooreman, N.G. and Lee, J. and Wu, H. and Hu, S. and Churko, J.M. and Diecke, S. and Burridge, P.W. and He, C. and Barron, F.E. and Ong, S.G. and Gold, J.D. and Wu, J.C
Abstract:AIMS: High-fat diet-induced obesity (DIO) is a major contributor to type II diabetes and micro- and macro-vascular complications leading to peripheral vascular disease (PVD). Metabolic abnormalities of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from obese individuals could potentially limit their therapeutic efficacy for PVD. The aim of this study was to compare the function of iPSC-ECs from normal and DIO mice using comprehensive in vitro and in vivo assays. METHODS AND RESULTS: Six-week-old C57Bl/6 mice were fed with a normal or high-fat diet. At 24 weeks, iPSCs were generated from tail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayer approach. In vitro functional analysis revealed that iPSC-ECs from DIO mice had significantly decreased capacity to form capillary-like networks, diminished migration, and lower proliferation. Microarray and ELISA confirmed elevated apoptotic, inflammatory, and oxidative stress pathways in DIO iPSC-ECs. Following hindlimb ischaemia, mice receiving intramuscular injections of DIO iPSC-ECs had significantly decreased reperfusion compared with mice injected with control healthy iPSC-ECs. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving DIO iPSC-ECs. When pravastatin was co-administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, N(?)-nitro-l-arginine methyl ester. CONCLUSION: This is the first study to provide evidence that iPSC-ECs from DIO mice exhibit signs of endothelial dysfunction and have suboptimal efficacy following transplantation in a hindlimb ischaemia model. These findings may have important implications for future treatment of PVD using iPSC-ECs in the obese population.
Keywords:Diet-Induced Obesity, Induced Pluripotent Stem Cells, Endothelial Cells, Hindlimb Ischaemia, Statins, Peripheral Vascular Disease, Animals, Mice
Source:European Heart Journal
Publisher:Oxford University Press
Page Range:806-16
Date:1 April 2015
Official Publication:https://doi.org/10.1093/eurheartj/ehu411
PubMed:View item in PubMed

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