Inhibition of Intercellular Communication via Gap Junction in Cultured Aortic Endothelial Cells by Elevated Glucose and Phorbol Ester

Inoguchi, Toyoshi; Ueda, Fusao; Umeda, Fumio; Yamashita, Tsukasa; Nawata, Hajime

doi:10.1006/bbrc.1995.1365

Cited by 47 publications

(33 citation statements)

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“…In accordance with these findings, high glucose concentrations inhibited gap-junction dye transfer through the activation of a PKCdependent signaling pathway in cultured bovine aortic endothelial cells (94,95). In addition, exposure to a highglucose medium reduced gap-junction activity in rat microvascular endothelial cells (167), and the reduction in dye coupling observed in these cells was correlated with a decrease in Cx43 mRNA and protein levels (Fig.…”

Section: Diabetessupporting

confidence: 82%

Gap Junctions in the Control of Vascular Function

Figueroa

Duling

2009

Antioxidants & Redox Signaling

248

265

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Direct intercellular communication via gap junctions is critical in the control and coordination of vascular function. In the cardiovascular system, gap junctions are made up of one or more of four connexin proteins: Cx37, Cx40, Cx43, and Cx45. The expression of more than one gap-junction protein in the vasculature is not redundant. Rather, vascular connexins work in concert, first during the development of the cardiovascular system, and then in integrating smooth muscle and endothelial cell function, and in coordinating cell function along the length of the vessel wall. In addition, connexin-based channels have emerged as an important signaling pathway in the astrocyte-mediated neurovascular coupling. Direct electrical communication between endothelial cells and vascular smooth muscle cells via gap junctions is thought to play a relevant role in the control of vasomotor tone, providing the signaling pathway known as endothelium-derived hyperpolarizing factor (EDHF). Consistent with the importance of gap junctions in the regulation of vasomotor tone and arterial blood pressure, the expression of connexins is altered in diseases associated with vascular complications. In this review, we discuss the participation of connexin-based channels in the control of vascular function in physiologic and pathologic conditions, with a special emphasis on hypertension and diabetes. Antioxid. Redox Signal. 11, 251-266. 251

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Section: Diabetessupporting

confidence: 82%

Gap Junctions in the Control of Vascular Function

Figueroa

Duling

2009

Antioxidants & Redox Signaling

248

265

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“…Transformation, proliferation, migration to endomembrane of arteries, and lipid phagocytosis of VSMCs are steps in atherosclerotic plaque formation. It was formed that after the transformation of VSMC from differentiated contractile state to the activated synthetic state, the expression of Cx43 in VSMC increased sixfold and GJ diameter was enlarged (Inoguchi et al, 1995). Study showed that the expression of Cx43 at the thickened site of the endomembrane during early arteriosclerosis was highly elevated (Blackburn et al, 1995).…”

Section: Discussionmentioning

confidence: 93%

Effects of angiotensin II on connexin 43 of VSMCs in arteriosclerosis

Cai

Ruan

Wang

et al. 2006

J. Zhejiang Univ. - Sci. B

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Abstract:Objective: To observe the effect of angiotensin II (Ang II) on expression of gap junction channel protein connexin 43 (Cx43) in the proliferation process of vascular smooth muscle cells (VSMCs) during the early stage of arteriosclerosis. Methods: Thirty-two adult male rabbits were randomly divided into 4 groups. Rabbits in Group A were fed common diet while others in Groups B, C, and D were fed high-cholesterol diet. Losartan (10 mg/(kg⋅d)) and ramipril (0.5 mg/(kg⋅d)) were added in the diet of Groups C and D, respectively. The animals were sacrificed after 8 weeks and abdominal aortas were removed and dissected. The expression of Cx43 was assayed using RT-PCR and Western Blotting analysis. Results: Cx43 was increased markedly in both protein and mRNA level in Groups B, C, and D fed high-cholesterol diet compared with that in control group (P<0.01). Cx43 level in losartan or ramipril treated groups was higher than that in control group (P<0.01, P<0.05), but lower than that in high-cholesterol diet groups (P<0.05, P<0.01). Conclusion: Cx43 level was upregulated in VSMCs during early atherosclerosis. Losartan and ramipril can inhibit the expression of Cx43.

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“…Moreover, increased degradation of Cx43 results in a decrease in the amount of Cx43 available to form gap junctions at the plasma membrane, leading to a reduction in intercellular communication in endothelial cells. DISCUSSION Previous studies demonstrated that high glucose induces a reduction of GJIC (25)(26)(27)(28). More recently, Sato et al (11) showed that the decreased levels of Cx43 were partially associated with a down-regulation of Cx43 in response to hyperglycemia.…”

Section: Fig 3 Effect Of Phosphorylation On the Amount Of Cx43mentioning

confidence: 98%

“…For example, in retinal pigment epithelium (41), epididymal endothelial cells (11,27), and smooth muscle cells (25), it has been shown that high glucose reduced the intercellular communication. Significantly, the decrease in intercellular communication induced by high glucose, in most studies, can be reversed by PKC inhibitors (25,28,32), thus indicating that phosphorylation is the mechanism whereby hyperglycemia reduces intercellular communication.…”

Section: Fig 3 Effect Of Phosphorylation On the Amount Of Cx43mentioning

confidence: 99%

High Glucose Down-regulates Intercellular Communication in Retinal Endothelial Cells by Enhancing Degradation of Connexin 43 by a Proteasome-dependent Mechanism

Fernandes

Girão

Pereira

2004

Journal of Biological Chemistry

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Intercellular communication through gap junctions (GJIC) is most likely relevant to maintaining the integrity of the blood-retinal barrier. In this study, we investigated the mechanism whereby high glucose enhances degradation of connexin 43 (Cx43), thus contributing to a decrease in GJIC. The levels of Cx43 in bovine retinal endothelial cells exposed to high glucose (25 mM) decreased about 50% as compared with controls (5.5 mM glucose). Consistently, the half-life of the protein decreased from 2.3 to 1.9 h. The proteasome inhibitors MG132 and lactacystin prevented the loss of Cx43 induced by high glucose and extended Cx43 half-life. The amount of phosphorylated Cx43 increased in high glucose and after proteasome inhibition. Scrape-loading dye transfer experiments show that high glucose is associated to a decrease of 40% in GJIC. Significantly, this reduction can be reversed by proteasome inhibitors. The decrease in GJIC in cells exposed to high glucose is associated with a loss of Cx43 from the plasma membrane, as demonstrated by immunofluorescence and biotinylation of cell-surface proteins. Results indicate that increased phosphorylation of Cx43 under high glucose is the mechanism targeting Cx43 for degradation by a proteasome-dependent mechanism. Increased degradation of Cx43 and reduction of GJIC in high glucose may be of physiological importance by contributing to endothelial cell dysfunction associated with the breakdown of the blood-retinal barrier in diabetic retinopathy.

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Inhibition of Intercellular Communication via Gap Junction in Cultured Aortic Endothelial Cells by Elevated Glucose and Phorbol Ester

Cited by 47 publications

References 0 publications

Gap Junctions in the Control of Vascular Function

Gap Junctions in the Control of Vascular Function

Effects of angiotensin II on connexin 43 of VSMCs in arteriosclerosis

High Glucose Down-regulates Intercellular Communication in Retinal Endothelial Cells by Enhancing Degradation of Connexin 43 by a Proteasome-dependent Mechanism

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