scholarly journals Adaptation of the heart to hypertension is associated with maladaptive gap junction connexin-43 remodeling

2008 ◽  
pp. 7-11
Author(s):  
M Fialová ◽  
K Dlugošová ◽  
L Okruhlicová ◽  
F Kristek ◽  
M Manoach ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Gap Junctions ◽  
Gap Junction ◽  
Connexin 43 ◽  
Isolated Heart ◽  
Intercellular Junctions ◽  
Membrane Surfaces ◽  
Rat Hearts ◽  
Junction Protein ◽  
Heart Preparation

We hypothesized that hypertension-related myocardial remodeling characterized by hypertrophy and fibrosis might be accompanied by cell-to-cell gap junction alterations that may account for increased arrhythmogenesis. Intercellular junctions and expression of gap junction protein connexin-43 were analyzed in rat heart tissues from both spontaneous (SHR) and L-NAME model of hypertension. Isolated heart preparation was used to examine susceptibility of the heart to lethal ventricular fibrillation induced by low potassium perfusion. Ultrastructure observation revealed enhanced neoformation of side-to-side type while internalization of end-to-end type (intercalated disc-related) of gap junctions prevailed in the myocardium of rats suffering from either spontaneous or L-NAME-induced hypertension. In parallel, immunolabeling showed increased number of connexin43 positive gap junctions in lateral cell membrane surfaces, particularly in SHR. Besides, focal loss of immunopositive signal was observed more frequently in hearts of rats treated with L-NAME. There was a significantly higher incidence of hypokalemia-induced ventricular fibrillation in hypertensive compared to normotensive rat hearts. We conclude that adaptation of the heart to hypertension-induced mechanical overload results in maladaptive gap junction remodeling that consequently promotes development of fatal arrhythmias.

Analysis of distribution patterns of gap junctions during development of embryonic chick facial primordia and brain

Development ◽  
1991 ◽  
Vol 111 (2) ◽  
pp. 509-522
Author(s):  
R. Minkoff ◽  
S.B. Parker ◽  
E.L. Hertzberg
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Uniform Distribution ◽  
Rat Liver ◽  
Connexin 43 ◽  
Cell Communication ◽  
Exterior Surface ◽  
Junction Protein ◽  
Primary Palate ◽  
Gap Junction Protein

Gap junction distribution in the facial primordia of chick embryos at the time of primary palate formation was studied employing indirect immunofluorescence localization with antibodies to gap junction proteins initially identified in rat liver (27 × 10(3) Mr, connexin 32) and heart (43 × 10(3) Mr, connexin 43). Immunolocalization with antibodies to the rat liver gap junction protein (27 × 10(3) Mr) demonstrated a ubiquitous and uniform distribution in all regions of the epithelium and mesenchyme except the nasal placode. In the placodal epithelium, a unique non-random distribution was found characterized by two zones: a very heavy concentration of signal in the superficial layer of cells adjacent to the exterior surface and a region devoid of detectable signal in the interior cell layer adjacent to the mesenchyme. This pattern was seen during all stages of placode invagination that were examined. The separation of gap junctions in distinct cell layers was unique to the nasal placode, and was not found in any other region of the developing primary palate. One other tissue was found that exhibited this pattern-the developing neural epithelium of the brain and retina. These observations suggest the presence of region-specific signaling mechanisms and, possibly, an impedance of cell communication among subpopulations of cells in these structures at critical stages of development. Immunolocalization with antibodies to the ‘heart’ 43 × 10(3) Mr gap junction protein also revealed the presence of gap junction protein in facial primordia and neural epithelium. A non-uniform distribution of immunoreactivity was also observed for connexin 43.

Effects of diminished expression of connexin43 on gap junction number and size in ventricular myocardium

2000 ◽  
Vol 278 (5) ◽  
pp. H1662-H1670 ◽  
Author(s):  
Jeffrey E. Saffitz ◽  
Karen G. Green ◽  
William J. Kraft ◽  
Kenneth B. Schechtman ◽  
Kathryn A. Yamada
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Ventricular Myocytes ◽  
Intercellular Junctions ◽  
Ventricular Myocardium ◽  
Electron Microscopic ◽  
Confocal Immunofluorescence Microscopy ◽  
Normal Number ◽  
Gap Junction Channel ◽  
Junction Protein

Gap junction number and size vary widely in cardiac tissues with disparate conduction properties. Little is known about how tissue-specific patterns of intercellular junctions are established and regulated. To elucidate the relationship between gap junction channel protein expression and the structure of gap junctions, we analyzed Cx43 +/− mice, which have a genetic deficiency in expression of the major ventricular gap junction protein, connexin43 (Cx43). Quantitative confocal immunofluorescence microscopy revealed that diminished Cx43 signal in Cx43 +/− mice was due almost entirely to a reduction in the number of individual gap junctions (226 ± 52 vs. 150 ± 32 individual gap junctions/field in Cx43 +/+ and +/− ventricles, respectively; P < 0.05). The mean size of an individual gap junction was the same in both groups. Immunofluorescence results were confirmed with electron microscopic morphometry. Thus when connexin expression is diminished, ventricular myocytes become interconnected by a reduced number of large, normally sized gap junctions, rather than a normal number of smaller junctions. Maintenance of large gap junctions may be an adaptive response supporting safe ventricular conduction.

scholarly journals Amyloid-β regulates gap junction protein connexin 43 trafficking in cultured primary astrocytes

2020 ◽  
Vol 295 (44) ◽  
pp. 15097-15111
Author(s):  
Mahua Maulik ◽  
Lakshmy Vasan ◽  
Abhishek Bose ◽  
Saikat Dutta Chowdhury ◽  
Neelanjana Sengupta ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Connexin 43 ◽  
Cx43 Expression ◽  
Chemical Chaperone ◽  
Junction Protein ◽  
Gap Junction Coupling ◽  
Gap Junction Protein ◽  
Junction Coupling ◽  
And Function

Altered expression and function of astroglial gap junction protein connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). Although earlier studies have examined the effect of increased β-amyloid (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35-exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35-exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.

scholarly journals Bimodal inhibition of connexin 43 gap junctions decreases ACTH-induced steroidogenesis and increases bovine adrenal cell population growth

2001 ◽  
Vol 171 (1) ◽  
pp. 199-208 ◽  
Author(s):  
US Shah ◽  
SA Murray
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Growth Rates ◽  
Connexin 43 ◽  
Cell Populations ◽  
Adrenal Cell ◽  
Junction Protein ◽  
Acth Treatment ◽  
Cell Population Growth ◽  
Gap Junction Protein

In order to elucidate the role of gap junctions in adrenal cell responses, we measured the effect of inhibiting gap junctions with 18-alpha glycerrhetinic acid (GA; a potent inhibitor of cell-cell communication) and connexin antisense transfection on cell proliferation and adrenocorticotropin (ACTH)-stimulated steroidogenesis. In these experiments we utilized a bovine adrenocortical cell (SBAC) population, which responds to ACTH treatment with a dose-dependent increase in steroid production, an increase in connexin 43 (alpha(1)-Cx43) gap junction protein concentrations, and a decrease in cell population growth. SBAC cell populations treated with GA had increased growth rates, decreased ACTH-stimulated steroidogenesis, but no reduction in alpha(1)-Cx43 gap junction protein contents. In contrast, when SBAC cells were transfected with alpha(1)-Cx43 antisense cDNA, gap junction protein concentration was dramatically reduced as expected, unlike the GA-treated cell populations. Cell populations transfected with alpha(1)-Cx43-antisense also exhibited increased growth rates and a decreased steroidogenic response to ACTH treatment as compared with control or vector-only transfected cell populations. The decreased responsiveness and increased number of cells in the population after gap junction function was decreased by either GA treatment or antisense transfection, suggests that gap junctions may be necessary factors in ACTH-stimulated responsiveness and growth control in the adrenal gland.

Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release

2018 ◽  
Vol 119 (1) ◽  
pp. 305-311 ◽  
Author(s):  
Wei Chen ◽  
Yijun Guo ◽  
Wenjin Yang ◽  
Lei Chen ◽  
Dabin Ren ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Gap Junction ◽  
Connexin 43 ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Cx43 Expression ◽  
Term Potentiation ◽  
Junction Protein

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using Western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results imply that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release. NEW & NOTEWORTHY We have demonstrated in rat traumatic brain injury (TBI) models that both phosphorylated connexin 43 (p-Cx43) expression and exosome release were elevated in the hippocampus following TBI. The promoted exosome release depends on the phosphorylation of Cx43 and requires ERK signaling activation. Exosome treatment could partially restore the attenuated long-term potentiation. Our results provide new insight for future therapeutic direction on the functional recovery of TBI by promoting p-Cx43-dependent exosome release but limiting the gap junction-mediated bystander effect.

scholarly journals Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts

2011 ◽  
Vol 301 (1) ◽  
pp. H180-H191 ◽  
Author(s):  
Norishige Morita ◽  
Jong-Hwan Lee ◽  
Aneesh Bapat ◽  
Michael C. Fishbein ◽  
William J. Mandel ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Connexin 43 ◽  
Left Ventricular ◽  
Triggered Activity ◽  
Adult Rat ◽  
Rat Hearts ◽  
Intracellular Calcium Ion ◽  
Dependent Protein ◽  
Isolated Cardiac Myocytes ◽  
Delayed Afterdepolarizations

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Cai2+) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (∼4 mo) and aged (∼24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Cai2+ transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (KATP) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial KATP block. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF ( P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts ( P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of KATP channels CaMKII and NCX.

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