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Isoflavone genistein protects human vascular endothelial cells against tumor necrosis factor-α-induced apoptosis through the p38β mitogen-activated protein kinase

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Abstract

Isoflavone genistein may have beneficial effects on vascular function, but the mechanism is unclear. Here, we investigated whether genistein protects vascular endothelial cells against apoptosis induced by tumor necrosis factor-α. We show that genistein significantly inhibited TNF-α-induced apoptosis in human aortic endothelial cells as determined by caspase-3 activation, 7-amino actinomycin D staining, in situ apoptotic cell detection and DNA laddering. The anti-apoptotic effect of genistein was associated with an enhanced expression of Bcl-2 protein and its promoter activity. Inhibition of extracellular signal-regulated kinase 1/2, protein kinase A, or estrogen receptors had no effect on the cytoprotective effect of genistein. However, inhibition of p38 mitogen-activated protein kinase (p38) completely abolished this genistein effect. Accordingly, stimulation of HAECs with genistein resulted in rapid activation of p38β, but not p38α. These findings provide the evidence that genistein acts as a survival factor for vascular ECs to protect cells against apoptosis via activation of p38β. Preservation of the functional integrity of the endothelial monolayer may represent an important mechanism by which genistein exerts its vasculoprotective effect.

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Abbreviations

7-AAD:

7-Amino actinomycin D

CREB:

cAMP-Responsive element binding protein

DMSO:

Dimethylsulfoxide

ECs:

Endothelial cells

ERs:

Estrogen receptors

ERK1/2:

Extracellular signal-regulated kinase 1/2

FBS:

Fetal bovine serum

HAECs:

Human aortic endothelial cells

LDL:

Low density lipoprotein

p38:

p38 Mitogen-activated protein kinase

p38α:

p38 Mitogen-activated protein kinase alpha

p38β:

p38 Mitogen-activated protein kinase beta

PBS:

Phosphate-buffered saline

PKA:

Protein kinase A

PTK:

Protein tyrosine kinase

TNF-α:

Tumor necrosis factor-alpha

TUNEL:

Terminal deoxynucleotidyltransferase dUTP nick-end labeling

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Acknowledgments

This work was supported by grants from the American Heart Association Mid-Atlantic Affiliate (to D. Liu), the National Center for Complementary and Alternative Medicine of the National Institute of Health (5R21AT002739 and 1R21AT004694 to D. Liu), Diabetes Action Research and Education Foundation (to D. Liu) and the John Lee Pratt Fellowship (to H. Si) from Virginia Polytechnic Institute and State University.

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  1. Department of Human Nutrition, Foods and Exercise, College of Agriculture and Life Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA

    Hongwei Si & Dongmin Liu

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Correspondence to Dongmin Liu.

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Si, H., Liu, D. Isoflavone genistein protects human vascular endothelial cells against tumor necrosis factor-α-induced apoptosis through the p38β mitogen-activated protein kinase. Apoptosis 14, 66–76 (2009). https://doi.org/10.1007/s10495-008-0283-9

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