Altered gap junction activity in cardiovascular tissues of diabetes

Inoguchi, Toyoshi; Hai, Yu; Imamura, Minako; Kakimoto, Maiko; Kuroki, Tatsuya; Maruyama, Toru; Nawata, Hajime

doi:10.1007/s007950170002

Cited by 52 publications

(49 citation statements)

References 20 publications

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“…As the first step, we evaluated whether high glucose affected GMC connexin expression and GJIC activity. The results showed that Cx43 expression and the number of Cx43 gap junctions were significantly downregulated by high glucose, which was consistent with some previous results (8,9,11,32). Cx43 family members degrade rapidly, with half-lives of only 1.5 to 5 h (21), suggesting that the reduction of Cx43 expression could be attributed to decreased transcription and translation of Cx43 gene in high glucose.…”

Section: Discussionsupporting

confidence: 91%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P < 0.05) but also increased the percentage of senescence-associated ␤-galactosidase (SA-␤-gal) stained cells and expression of p21 cip1 and p27 kip1 (P < 0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-␤-gal stained cells and p27 kip1 and p21 cip1 expression in GMC (P < 0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-␤-gal stained cells (P < 0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.

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Section: Discussionsupporting

confidence: 91%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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“…Cell cultures exposed to high glucose levels have been used to study gap junctions and specific connexins in isolation, with results showing attenuation of gap junction activity in bovine aortic endothelial and smooth muscle cells [22,23]. Furthermore, investigations using animal models of type 1 diabetes have shown attenuation of EDHF-mediated responses [24] and gap junction activity in mesenteric [25] arteries from streptozotocin (STZ)-induced diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

et al. 2008

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Aims/hypothesis The objective of this study was to examine the effect of insulin resistance on endothelium-derived hyperpolarising factor (EDHF) and small mesenteric artery endothelial function using 25-week-old insulin-resistant obese Zucker rats (OZRs) and lean littermate control rats (LZRs). The involvement of gap junctions and their connexin subunits in the EDHF relaxation response was also assessed. Methods Mesenteric arteries were evaluated using the following assays: (1) endothelial function by pressure myography, with internal diameter recorded using video microscopy; (2) connexin protein levels by western blotting; and (3) Cx mRNA expression by real-time PCR. Results Relaxations in response to acetylcholine were significantly smaller in mesenteric arteries from the OZRs than the LZRs, whereas there was no difference in relaxations in response to levcromakalim. Responses to acetylcholine were not altered by nitric oxide inhibitors, but were abolished by charybdotoxin in combination with apamin, which blocked the EDHF component of the response. 40 Gap27 significantly attenuated the response to acetylcholine in the LZRs, but had no effect in the OZRs. Connexin 40 protein and Cx40 mRNA levels in mesenteric vascular homogenates were significantly smaller in the OZRs than in the LZRs, with no difference in connexin 43 or Cx43 mRNA levels. Conclusions/interpretation These findings demonstrate that endothelial dysfunction in mesenteric arteries from the insulin-resistant OZRs can be attributed to a defect in EDHF. The results also suggest that the defective EDHF is at least partly related to an impairment of connexin 40-associated gap junctions, through a decrease in connexin 40 protein and Cx40 mRNA expression in the OZRs.

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“…1). The expression of connexins has been reported to be altered in several animals models of pathologies associated with vascular complications (15), such as hypertension (56,159) and diabetes (95,215), which highlights the importance of the direct cell-to-cell interaction for vascular homeostasis.…”

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confidence: 99%

Gap Junctions in the Control of Vascular Function

Figueroa

Duling

2009

Antioxidants & Redox Signaling

249

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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Altered gap junction activity in cardiovascular tissues of diabetes

Cited by 52 publications

References 20 publications

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

Gap Junctions in the Control of Vascular Function

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