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.
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.


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-1alpha 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.
Park
Cheol Whee
CW
Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Kim
Hyung Wook
HW
Lim
Ji Hee
JH
Yoo
Ki Dong
KD
Chung
Sungjin
S
Shin
Seok Joon
SJ
Chung
Hyun Wha
HW
Lee
Sang Ju
SJ
Chae
Chi-Bom
CB
Kim
Yong-Soo
YS
Chang
Yoon Sik
YS
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000473:pathology / Q000517:prevention & control*; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C501225:arginyl-arginyl-lysyl-arginyl-arginyl-arginine; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D003849:Deoxyguanosine
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