Vascular Endothelial Growth Factor Inhibition by dRK6 Causes Endothelial Apoptosis, Fibrosis, and Inflammation in the Heart via the Akt/eNOS Axis in db/db Mice

  1. Cheol Whee Park1,
  2. Hyung Wook Kim1,
  3. Ji Hee Lim1,
  4. Ki Dong Yoo1,
  5. Sungjin Chung1,
  6. Seok Joon Shin1,
  7. Hyun Wha Chung1,
  8. Sang Ju Lee1,
  9. Chi-Bom Chae2,
  10. Yong-Soo Kim1 and
  11. Yoon Sik Chang1
  1. 1Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
  2. 2Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
  1. Corresponding author: Yoon Sik Chang, ysc543{at}unitel.co.kr.

Abstract

OBJECTIVE Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes.

RESEARCH DESIGN AND METHODS We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db/db and db/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db/db-dRK6 and db/m-dRK6) or were untreated.

RESULTS Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1α expression were significantly increased. No such changes were found in the other groups, including the db/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress.

CONCLUSIONS Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received January 30, 2009.
    • Accepted July 24, 2009.
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  1. Diabetes vol. 58 no. 11 2666-2676
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