Reciprocal Regulation between Proinflammatory Cytokine-induced Inducible NO Synthase (iNOS) and Connexin43 in Bladder Smooth Muscle Cells

Li, Kai; Yao, Jian; Shi, Liye; Sawada, Norifumi; Chi, Yuan; Yan, Qiaojing; Matsue, Hiroyuki; Kitamura, Masanori; Takeda, Masayuki

doi:10.1074/jbc.m111.274449

Cited by 33 publications

(42 citation statements)

References 53 publications

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“…6A). To specifically assess gap junction function and intracellular communication between connecting NMVMs, we then performed dye microinjection studies as well as scrape loading assays (Boswell et al, 2009;elFouly et al, 1987;Li et al, 2011;Opsahl and Rivedal, 2000) ( Fig. 6B,C) .…”

Section: Vcl Reduction Causes a Decrease In Gap Junctional Communicationmentioning

confidence: 99%

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Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Zemljic-Harpf

Godoy

Platoshyn

et al. 2014

Journal of Cell Science

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Vinculin (Vcl) links actin filaments to integrin-and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1, also known as TJP1) binds connexin-43 (Cx43, also known as GJA1), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Given that loss of Vcl from cardiomyocytes causes maldistribution of Cx43 and predisposes cardiomyocyte-specific Vcl-knockout mice with preserved heart function to arrhythmia and sudden death, we hypothesized that Vcl and ZO-1 interact and that loss of this interaction destabilizes gap junctions. We found that Vcl, Cx43 and ZO-1 colocalized at the intercalated disc. Loss of cardiomyocyte Vcl caused parallel loss of ZO-1 from intercalated dics. Vcl coimmunoprecipitated Cx43 and ZO-1, and directly bound ZO-1 in yeast two-hybrid studies. Excision of the Vcl gene in neonatal mouse cardiomyocytes caused a reduction in the amount of Vcl mRNA transcript and protein expression leading to (1) decreased protein expression of Cx43, ZO-1, talin, and b1D-integrin, (2) reduced PI3K activation, (3) increased activation of Akt, Erk1 and Erk2, and (4) cardiomyocyte necrosis. In summary, this is the first study showing a direct interaction between Vcl and ZO-1 and illustrates how Vcl plays a crucial role in stabilizing gap junctions and myocyte integrity.

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Section: Vcl Reduction Causes a Decrease In Gap Junctional Communicationmentioning

confidence: 99%

“…They were then rinsed three times with PBS, and incubated for an additional 20 min in the culture medium saved prior to dye loading. Dye transfer was then assessed by image acquisition 25 min after dye loading, and analyzed as previously described (Boswell et al, 2009;el-Fouly et al, 1987;Li et al, 2011;Opsahl and Rivedal, 2000).…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Zemljic-Harpf

Godoy

Platoshyn

et al. 2014

Journal of Cell Science

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“…Cx43 is up-regulated in various tissues and cells by inflammatory stimuli. 9,16 We have previously revealed that expression of Cx43 in rat fibroblastlike synoviocytes was increased by stimulation with lipopolysaccharide. We also showed that the expression of Cx43 was enhanced in synovial tissue from rats with the collagen-induced arthritis (CIA) model of RA.…”

Section: Discussionmentioning

confidence: 99%

“…6 Cx43 plays an important role in the regulation of various immune inflammatory processes. [7][8][9] In the nervous system, silencing the Cx43 gene down-regulates the inflammatory response, 10 while a gap junction blocker (heptanol) inhibits the production of TNF-a in RA synovial tissue. 11 These reports suggest that the expression of Cx43 in synovial tissue may be involved in RA pathophysiology.…”

Section: 2mentioning

confidence: 99%

Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis

et al. 2016

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“…Bladder disturbances are one condition that can manifest in the young, but it is not clear whether this is linked to a specific mutation site in the Cx43 gene, or if neurogenic or myogenic changes in the bladder are responsible. Since Cx43 is abundantly expressed in BSMCs (bladder smooth muscle cells) [7–10] and interstitial cells [11], but not found in neurons or the skeletal muscle cells of the sphincter, we propose that the bladder defect would have a myogenic origin. In order to address this question, two genetically modified mouse lines that mimic ODDD (Cx43 G60S and Cx43 I130T ) were acquired [12,13].…”

Section: Introductionmentioning

confidence: 99%

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia

Huang

Shao

Barr

et al. 2014

Biochemical Journal

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To date, over 65 mutations in the gene encoding Cx43 (connexin43) have been linked to the autosomal-dominant disease ODDD (oculodentodigital dysplasia). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. BSMCs (bladder smooth muscle cells) from wild-type and two Cx43 mutant lines (Cx43G60S and Cx43I130T) that mimic ODDD exhibit a significant reduction in total Cx43. Dye transfer studies revealed that the G60S mutant was a potent dominant-negative inhibitor of co-expressed Cx43, a property not equally shared by the I130T mutant. BSMCs from both mutant mouse strains were defective in their ability to contract, which is indicative of phenotype changes due to harbouring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in controls and mutants containing BSMCs, but the non-muscle myosin heavy chain A levels were only reduced in cells from control mice. Although the Cx43G60S mutant mice showed no difference in voided urine volume or frequency, the Cx43I130T mice voided less frequently. Thus, similar to the diversity of morbidities seen in ODDD patients, genetically modified mice also display mutation-specific changes in bladder function. Furthermore, although mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43I130T mice are likely to be complemented by neurogenic changes.

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Reciprocal Regulation between Proinflammatory Cytokine-induced Inducible NO Synthase (iNOS) and Connexin43 in Bladder Smooth Muscle Cells

Cited by 33 publications

References 53 publications

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia

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