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Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose

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Abstract

The underlying molecular mechanism whereby hyperglycemia causes endothelial cell apoptosis is not well understood. This study aims to elucidate the role of survival factor VEGF involved in the apoptosis of endothelial cells induced by elevated glucose. The present study confirmed that high concentration of glucose (25 mmol/l) significantly increased the apoptotic cell number in cultured primary human umbilical vein endothelial cells (HUVEC). Up-regulation of Bax/Bcl-2 ratio and activation of caspase-3 induced by high glucose suggested that mitochondria apoptosis pathway was involved. High glucose significantly reduced VEGF expression in HUVEC both at mRNA and protein levels. p42/44 MAPK phosphorylation was transitory attenuated when exposed to high glucose and preceded VEGF reduction, thus suggesting down-regulation of VEGF through inhibition of p42/44 MAPK. Addition of VEGF prevented HUVEC apoptosis from high glucose exposure. Moreover, elevated reactive oxygen species (ROS) generation, calcium overload, Bax/Bcl-2 ratio, caspase-3 activation in HUVEC induced by high glucose were reversed by pre-challenge with VEGF. This may represent a mechanism for the anti-apoptotic effect of VEGF. These results suggest that down-regulation of VEGF plays a critical role in apoptosis of endothelial cells induced by high glucose and restoration of VEGF might have benefits in the early stage of diabetic endothelial dysfunction.

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Abbreviations

Glc:

Glucose

HUVEC:

Human umbilical vein endothelial cells

MAPK:

Mitogen-activated protein kinase

ROS:

Reactive oxygen species

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This study was supported by National Nature Science Foundation of China, Grant Number: 30370313, 30570372, 30600724, 30700120; CMB(China Medical Board of New York, Inc.); Program for New Century Excellent Talents in University, Grant Number: NCET-040792; Program for Doctoral Station in University, Grant Number: 20070558209,20070558215; Team Project of Nature Science Foundation of Guangdong Province, China, Grant Number: 06201946; Key Sci-tech Research Project of Guangdong Province, China, Grant Number: 2005A10902003, 2006B35502001; Nature Science Foundation of Guangdong Province, China, Grant Number: 06021260; Key Sci-tech Research Project of Guangzhou Municipality, Guangdong Province, China, Grant Number: 2006Z3-E4111, 2007Z3-E5041.

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Authors and Affiliations

  1. Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China

    Zhonghan Yang, Qing Gong, Xia Yang, Weibin Cai & Guoquan Gao

  2. Department of Anatomy, Zhongshan Medical School, Sun Yat-sen University, Guangzhou, 510080, China

    Xuehua Mo & Yunshao He

  3. Medical Research Center of the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Qiuhui Pan

  4. China Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China

    Weibin Cai

  5. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Chaoyang Li

  6. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA

    Jian-xing Ma

  7. Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism, Office of Education, Sun Yat-sen University, Guangzhou, 510080, China

    Guoquan Gao

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  1. Zhonghan Yang
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  2. Xuehua Mo
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  3. Qing Gong
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  5. Xia Yang
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  9. Yunshao He
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Correspondence to Guoquan Gao.

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Zhonghan Yang, Xuehua Mo, and Qing Gong have contributed equally to this study.

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Yang, Z., Mo, X., Gong, Q. et al. Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose. Apoptosis 13, 1331–1343 (2008). https://doi.org/10.1007/s10495-008-0257-y

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