Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium*

Rignault, Stéphanie; Haefliger, Jacques‐Antoine; Gasser, Didier; Markert, Michèle; Nicod, Pascal; Liaudet, Lucas; Waeber, Bernard; Feihl, François

doi:10.1097/01.ccm.0000165968.47343.0d

Cited by 22 publications

(15 citation statements)

References 42 publications

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“…Currently, of the 21 identified connexins, only Cx37, Cx40, and Cx43 have been shown to be expressed in the endothelial layer of the vasculature (Haefliger et al, 2004). Here, similar to our recent reports (Bolon et al, , 2007, Cx40 has been shown to critically participate in vascular function (de Wit et al, 2000;Simon et al, 2004;Rignault et al, 2005). Gap junctional coupling can be modulated by several factors including altered phosphorylation of connexins, voltage and chemical gating, and/or altered connexin protein expression (van Veen et al, 2006).…”

supporting

confidence: 81%

“…It has been shown in a mouse model of sepsis, that decreased endothelial dye coupling correlated with decreased Cx40 protein expression at 18 h post-LPS (Simon et al, 2004). Additionally, recovery of impaired endothelium-dependent relaxation 12-24 h after the onset of sepsis correlated with increased Cx40 protein expression (Rignault et al, 2005). We have further shown, through the use of the various connexin mutant mice, that acute decreases in electrical coupling following H/R or LPS exposure are Cx40-dependent (Bolon et al, , 2007.…”

Section: Discussionmentioning

confidence: 89%

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Lipopolysaccharide plus hypoxia and reoxygenation synergistically reduce electrical coupling between microvascular endothelial cells by dephosphorylating Connexin40

Bolon

Peng

Kidder

et al. 2008

Journal Cellular Physiology

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We showed that lipopolysaccharide (LPS) or hypoxia and reoxygenation (H/R) decreases electrical coupling between microvascular endothelial cells by targeting the gap junction protein connexin40 (Cx40), tyrosine kinase-, ERK1/2-, and PKA-dependently. Since LPS can compromise microvascular blood flow, resulting in micro-regional H/R, the concurrent LPS + H/R could reduce coupling to a much greater extent than LPS or H/R alone. We examined this possibility in a model of cultured microvascular endothelial cells (mouse skeletal muscle origin) in terms of electrical coupling and the phosphorylation status of Cx40. To assess coupling, we measured the spread of electrical current injected into the cell monolayer and computed the intercellular resistance as an inversed measure of coupling. In wild type cells, but not in Cx40 null cells, concurrent LPS + H/R synergistically increased resistance by approximately 270%, well above the level observed for LPS or H/R alone. Cx37 and Cx43 protein expression did not differ between Cx40 null and wild type cells. LPS + H/R increased resistance PKA- and PKC-dependently. By immunoprecipitating Cx40, we found that LPS + H/R reduced serine phosphorylation to a much greater degree than that observed for LPS or H/R alone. Further, PKA-specific, but not PKC-specific serine phosphorylation of Cx40 was also significantly reduced following LPS + H/R. This reduction was prevented by tyrosine kinase and MEK1/2 inhibition, by PKA activation, and mimicked in control cells by PKA inhibition. We conclude that LPS + H/R initiates tyrosine kinase- and ERK1/2-sensitive signaling that synergistically reduces inter-endothelial electrical coupling by dephosphorylating PKA-specific serine residues of Cx40.

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supporting

confidence: 81%

Section: Discussionmentioning

confidence: 89%

Lipopolysaccharide plus hypoxia and reoxygenation synergistically reduce electrical coupling between microvascular endothelial cells by dephosphorylating Connexin40

Bolon

Peng

Kidder

et al. 2008

Journal Cellular Physiology

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“…The thoracic aorta was carefully cleaned of adherent connective tissues and dissected in sterilized phosphate‐buffered saline (PBS) containing RNase inhibitor. Aortic ECs were harvested by gentle scraping using sterile surgical blades . Expression levels of miR‐375, RASD1, ERα, and Bcl‐2 in the aortic ECs were determined using qRT‐PCR and Western blotting.…”

Section: Methodsmentioning

confidence: 99%

Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA‐375, RASD1, and ERα

Chen

Zhang

Wang

et al. 2018

Molecular Carcinogenesis

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For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen formononetin, but how formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by formononetin. These results suggest selective action of formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why formononetin may not increase the risk of postmenopausal breast cancer.

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“…Tumor necrosis factor (TNF)-α exposure resulted in down-regulation of Cx37 and Cx40 mRNA, whereas Cx43 mRNA was unaffected, and transforming growth factor (TGF)-β1 exposure increased Cx43 and decreased Cx37 (Larson et al 1997;van Rijen et al 1998). Finally, sepsis induced in a rat model affected Cx40 mRNA but not Cx37 or Cx43 (Rignault et al 2005).…”

mentioning

confidence: 90%

Endothelial Connexin 37, Connexin 40, and Connexin 43 Respond Uniquely to Substrate and Shear Stress

Johnson

Nerem

2007

Endothelium

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Endothelial connexins have been linked to atherosclerosis and hypertension; however, little is know about their sensitivity to stimuli and individual functions. This study investigates the responses of endothelial connexin 37, connexin 40, and connexin 43 (Cx37, Cx40, and Cx43) to shear stress and substrate. Human endothelial cells were seeded on adsorbed collagen or a collagen gel containing smooth muscle cells and exposed to static or laminar shear stress. Connexin mRNA, protein, and gap junction communication were examined. Endothelial monolayers were treated with connexin-specific short interfering RNA (siRNA) and evaluated for communication, proliferation, and morphology under static and shear stress. Results show differential responses of Cx37, Cx40, and Cx43 to substrate and shear stress with reduced communication after shear exposure. RNA interference of individual connexins resulted in expression change of nontarget connexins, which suggests linked expression. Gap junction communication under static conditions is reduced following Cx43 siRNA treatment. Endothelial cells are more elongated with RNA interference (RNAi) targeting Cx40. In conclusion, endothelial connexins demonstrated novel sensitivity to mechanical environment and substrate. Individual isotypes show differential responses and RNAi knockdown provides new insight into connexin function and potential roles in the vasculature.

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Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium*

Abstract: In this experimental model, recovery from an early transient dysfunction of the aortic endothelium is associated with an enhanced expression of aortic endothelial Cx40.

Cited by 22 publications

References 42 publications

Lipopolysaccharide plus hypoxia and reoxygenation synergistically reduce electrical coupling between microvascular endothelial cells by dephosphorylating Connexin40

Lipopolysaccharide plus hypoxia and reoxygenation synergistically reduce electrical coupling between microvascular endothelial cells by dephosphorylating Connexin40

Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA‐375, RASD1, and ERα

Endothelial Connexin 37, Connexin 40, and Connexin 43 Respond Uniquely to Substrate and Shear Stress

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