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

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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., Mordwinkin, N.M., Kooreman, N.G., Lee, J., Wu, H., Hu, S., Churko, J.M., Diecke, S., Burridge, P.W., He, C., Barron, F.E., Ong, S.G., 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
ISSN:	0195-668X
Publisher:	Oxford University Press
Volume:	36
Number:	13
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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