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

Mingxia Gu, Nicholas M. Mordwinkin, Nigel G. Kooreman, Jaecheol Lee, Haodi Wu, Shijun Hu, Jared M. Churko, Sebastian Diecke, Paul W. Burridge, Chunjiang He, Frances E. Barron, Sang Ging Ong, Joseph D. Gold, Joseph C. Wu

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Aims High-fat diet-induced obesity (DIO) is amajor contributor to type II diabetes and micro- andmacro-vascular complications leading to peripheral vascular disease (PVD).Metabolic abnormalities of induced pluripotent stemcell-derived endothelial cells (iPSC-ECs) fromobese individuals could potentially limit their therapeutic efficacy forPVD.The aimof this studywas 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 micewere fed with a normal or high-fat diet. At 24weeks, iPSCs were generated fromtail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayerapproach. In vitro functional analysis revealed that iPSCECs 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 reperfusionwas observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, Nv-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. Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2014.

Original languageEnglish (US)
Pages (from-to)806-816
Number of pages11
JournalEuropean Heart Journal
Volume36
Issue number13
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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Pravastatin
Induced Pluripotent Stem Cells
Nitric Oxide
Endothelial Cells
Obesity
Diet
Hindlimb
Peripheral Vascular Diseases
High Fat Diet
Ischemia
Muscular Atrophy
Intramuscular Injections
Nitric Oxide Synthase
Type 2 Diabetes Mellitus
Reperfusion
Blood Vessels
Oxidative Stress
Fibroblasts
Transplantation
Enzyme-Linked Immunosorbent Assay

Keywords

  • Diet-induced obesity
  • Endothelial cells
  • Hindlimb ischaemia
  • Induced pluripotent stem cells
  • Peripheral vascular disease
  • Statins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism. / Gu, Mingxia; Mordwinkin, Nicholas M.; Kooreman, Nigel G.; Lee, Jaecheol; Wu, Haodi; Hu, Shijun; Churko, Jared M.; Diecke, Sebastian; Burridge, Paul W.; He, Chunjiang; Barron, Frances E.; Ong, Sang Ging; Gold, Joseph D.; Wu, Joseph C.

In: European Heart Journal, Vol. 36, No. 13, 01.04.2015, p. 806-816.

Research output: Contribution to journalArticle

Gu, M, Mordwinkin, NM, Kooreman, NG, Lee, J, Wu, H, Hu, S, Churko, JM, Diecke, S, Burridge, PW, He, C, Barron, FE, Ong, SG, Gold, JD & Wu, JC 2015, 'Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism', European Heart Journal, vol. 36, no. 13, pp. 806-816. https://doi.org/10.1093/eurheartj/ehu411
Gu, Mingxia ; Mordwinkin, Nicholas M. ; Kooreman, Nigel G. ; Lee, Jaecheol ; Wu, Haodi ; Hu, Shijun ; Churko, Jared M. ; Diecke, Sebastian ; Burridge, Paul W. ; He, Chunjiang ; Barron, Frances E. ; Ong, Sang Ging ; Gold, Joseph D. ; Wu, Joseph C. / Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism. In: European Heart Journal. 2015 ; Vol. 36, No. 13. pp. 806-816.
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AU - Mordwinkin, Nicholas M.

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AU - Lee, Jaecheol

AU - Wu, Haodi

AU - Hu, Shijun

AU - Churko, Jared M.

AU - Diecke, Sebastian

AU - Burridge, Paul W.

AU - He, Chunjiang

AU - Barron, Frances E.

AU - Ong, Sang Ging

AU - Gold, Joseph D.

AU - Wu, Joseph C.

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N2 - Aims High-fat diet-induced obesity (DIO) is amajor contributor to type II diabetes and micro- andmacro-vascular complications leading to peripheral vascular disease (PVD).Metabolic abnormalities of induced pluripotent stemcell-derived endothelial cells (iPSC-ECs) fromobese individuals could potentially limit their therapeutic efficacy forPVD.The aimof this studywas 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 micewere fed with a normal or high-fat diet. At 24weeks, iPSCs were generated fromtail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayerapproach. In vitro functional analysis revealed that iPSCECs 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 reperfusionwas observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, Nv-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. Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2014.

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KW - Peripheral vascular disease

KW - Statins

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