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Diabetes Metab J : Diabetes & Metabolism Journal

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3 "Diabetic angiopathy"
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Effect and Mechanism of High Glucose Level on the Expression of an Adhesion Protein, beta ig-h3, and Cellular Function in Endothelial Cells.
Sung Woo Ha, Hye Jin Yeo, Jong Sup Bae, Sung Chang Chung, Jung Guk Kim, In San Kim, In Kyu Lee, Bo Wan Kim
Korean Diabetes J. 2003;27(4):323-331.   Published online August 1, 2003
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BACKGROUND
Diabetes mellitus is a high risk condition for the development of atherosclerotic and thromboembolic macroangiopathy. There are many factors which are involved in development of these processes. Given the central pathogenic role of endotheliopathy in atherosclerosis, it is likely that this vascular monolayer is the ultimate target of injury in response to many cytokines and growth factors. A dysfunctional endothelium may contribute to the proatherogenic environment. Transforming growth factor (TGF-beta) is a key factor in the development of diabetic angiopathy and atherosclerosis because of its effect on the accumulation of extracellular matrix proteins and endothelial function. The adhesive molecule betaig-h3 is an extracellular matrix protein whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that betaig-h3 is a downstream target gene of TGF-beta, we hypothesized that betaig-h3 may also play a role in the development of diabetic angiopathy through its effect on the endothelial function. Therefore, we examined the effects of high glucose level on the expression of betaig-h3 and endothelial function in human umbilical vein endothelial cells (HUVECs). We also studied the mechanisms of this high glucose-induced betaig-h3 expression. METHODS: Endothelial cells were isolated from human umbilical cord and conditioned with different concentrations of TGF-beta or glucose. We measured TGF-beta and betaig-h3 protein presence/concentration/expression in cell supernatant by ELISA and examined whether TGF-beta is involved in high glucose-induced betaig-h3 expression. Finally, we investigated the biologic function of betaig-h3 in endothelial cells by using adhesion assay. RESULTS: Our study demonstrated that both high glucose level and TGF-beta induced betaig-h3 protein expression in HUVECs. High glucose level also induced TGF-beta protein expression in cells. Anti-TGF-beta antibody almost completely blocked high glucose-induced betaig-h3 expression. betaig-h3 was found to support the adhesion of endothelial cells. CONCLUSION: These results suggest that high glucose level upregulates betaig-h3 protein levels through the induction of TGF-beta and that betaig-h3 may play an important role in diabetic angiopathy by regulating adhesive function of endothelial cells.
Effect and Mechanism of Vascular Endothelial Growth Factor on Endothelial Nitric Oxide Synthase Expression in Aortic Endothelial Cells.
Soon Hee Lee, Jung Guk Kim, Joong Yeol Park, Sung Woo Ha, Bo Wan Kim
Korean Diabetes J. 2002;26(5):396-404.   Published online October 1, 2002
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AbstractAbstract PDF
BACKGROUND
Vascular endothelial growth factor (VEGF), a soluble angiogenic factor produced by many tumor and normal cells, is a potent angiogenic and vascular permeability factor. VEGF plays a key role in both pathological and physiological angiogenesis. There are many recent findings regarding the role of VEGF in diabetic microvascular and macrovascular diseases. Many approaches with VEGF-related therapies begin to treat and prevent these complications and have been used for the treatment of microvascular complications such as diabetic retinopathy, whereas VEGF agonists have been used to treat macrovascular complications such as myocardial infarction and peripheral limb ischemia. Nitric oxide (NO) is known to mediate many physiological and pathological functions, including modulation of vascular tone, permeability, and capillary growth. Recent reports indicate that NO may play an intimate role in VEGF signaling. Therefore, we hypothesized that the expression of eNOS may be regulated by VEGF. The objectives of the present study were to determine whether VEGF up-regulates the expression of endothelial NO synthase (eNOS) in endothelial cells and to elucidate the mechanism that mediate this response. METHODS: Endothelial cells were isolated from bovine aortae. The expression of eNOS was assessed by Northern blotting analysis. To evaluate the mechanism of VEGF-induced eNOS expression, endothelial cells were conditioned with VEGF and pretreated with phorbol-12-myristate acetate (PMA), a protein kinase C (PKC) activator, or GF109203X (GFX), a PKC inhibitor. The changes of eNOS gene expression. RESULTS: VEGF significantly increased the expression of eNOS mRNA in bovine aortic endothelial cells (BAEC) in time and dose dependent manners. PMA increased the expression of eNOS mRNA, as well as the VEGF-induced expression of eNOS mRNA in endothelial cells, while inhibition of the PKC activity, with the GFX blocked the upregulation of the VEGF-induced eNOS mRNA. CONCLUSION: The results suggest that VEGF upregulates eNOS gene expression in aortic endothelial cells, by a PKC dependent pathway and, eNOS may be important in the development of VEGF-induced angiopathy.
Effect of Transforming Growth Factor-Induced Gene Product, beta ig-h3 on Proliferation, Migration, and Adhesion of Aortic Smooth Muscle Cells Cultured in High Glucose.
Sung Woo Ha, Gui Hwa Jung, He Jin Yeo, Jong Sup Bae, Soon Hee Lee, Jung Guk Kim, Rang Woon Park, In San Kim, Bo Wan Kim
Korean Diabetes J. 2002;26(4):286-295.   Published online August 1, 2002
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AbstractAbstract PDF
BACKGROUND
Diabetes mellitus is associated with a substantial increase in the prevalence of atherosclerotic disease. There are many factors which are involved in development of these processes. Transforming growth factor (TGF-beta) is known to be an important factor in the pathogenesis of diabetic vascular complications. TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that beta ig-h3 is induced by TGF-beta, we hypothesized that beta ig-h3 may also play a role in the development of diabetic angiopathy. Then, we examined the effects of beta ig-h3 on biologic function of vascular smooth muscle cells (VSMCs) and potential roles of beta ig-h3 in the pathognesis of diabetic angiopathy. METHODS: VSMCs were isolated from rat thoracic aorta. We conditioned cells with different concentration of TGF-beta or glucose. We measured TGF-beta and beta ig-h3 protein in cell supernatant by ELISA. We also examined whether TGF-beta involves in high glucose-induced beta ig-h3 expression. Finally, we did proliferation, migration, and adhesion assay to investigate biologic function of beta ig-h3 in VSMCs. RESULTS: Our results demonstrated that TGF-beta induced beta ig-h3 expression in VSMCs in dose dependent manners. High glucose induced TGF expression as well as beta ig-h3 protein. Finally, beta ig-h3 was found to support the proliferation, migration, and adhesion of rat VSMCs. CONCLUSION: These results suggest that high glucose-and TGF-beta-induced beta ig-h3 may play an important role in diabetic angiopathy by regulating proliferation, migration, and adhesion of VSMCs.

Diabetes Metab J : Diabetes & Metabolism Journal
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