Dataset Information

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.

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-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.

SUBMITTER: Park CW

PROVIDER: S-EPMC2768173 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Park Cheol Whee CW 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

Diabetes 20090812 11

<h4>Objective</h4>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.<h4>Research design and methods</h4>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.<h ...[more]

PMID: 19675133

Similar Datasets

Project description:Aims: It is important to understand the mechanism that regulates post-ischemic angiogenesis and to explore a new therapeutic target for an effective improvement of revascularization in peripheral artery disease (PAD) patients. Post-ischemic angiogenesis is a highly orchestrated process, which involves vascular endothelial cells (ECs) proliferation, migration and assembly into capillaries. We found a significant reduction of S1pr2 (sphingosine 1-phosphate receptor 2) in endothelial cells after hindlimb ischemia (HLI). We thus hypothesized that EC-S1pr2 might be involved in the regulation of post-ischemic angiogenesis and blood flow recovery during peripheral arterial disease (PAD). Methods and Results: We generated both EC-specific S1pr2 loss-of-function and S1pr2 gain-of-function mice. Our study showed that EC-specific S1pr2 loss-of-function significantly enhanced post-ischemic angiogenesis and improved blood flow recovery upon femoral artery ligation, whereas the EC-specific S1pr2 gain-of-function severely hindered post-ischemic angiogenesis and reduced blood flow recovery in ischemic limbs. We next identified that S1pr2 inhibited AKT/eNOS signaling pathway, and thus inhibited EC proliferation/migration and angiogenic activity. As expected, pharmacological inhibition of S1pr2 by JTE013 improved post-ischemic angiogenesis and improved blood flow perfusion after femoral artery ligation. Moreover, we developed RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA which specifically targeted ECs and achieved an efficient silencing of S1pr2 expression in ECs in vivo. This EC-targeted strategy to dampen S1pr2 significantly enhanced post-ischemic angiogenesis and boosted blood perfusion after HLI, supplying a novel therapy target for patients with peripheral arterial disease. Conclusions: This present study demonstrates that EC-expressing S1pr2 tightly controls post-ischemic angiogenesis and blood flow perfusion recovery. This research provides a novel strategy for EC-target knockdown of S1pr2 as a new therapeutic intervention for patients with peripheral artery disease.

Dataset Information

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

Research design and methods

Results

Conclusions

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets