International Journal of Molecular Sciences

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Open AccessEditorial

Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases

by Juan C. Sáez and Colin Green

Int. J. Mol. Sci. 2018, 19(9), 2469; https://doi.org/10.3390/ijms19092469 - 21 Aug 2018

Cited by 12 | Viewed by 2885

Abstract

Over the last decade it has become evident that under normal conditions connexin hemichannels are either not expressed (e.g., skeletal muscle) or are expressed in very low numbers with low open probability in various mammalian tissues (e.g., liver and central nervous system (CNS)).[...] [...] Read more.

Over the last decade it has become evident that under normal conditions connexin hemichannels are either not expressed (e.g., skeletal muscle) or are expressed in very low numbers with low open probability in various mammalian tissues (e.g., liver and central nervous system (CNS)).[...] Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

Research

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16 pages, 5355 KiB

Open AccessArticle

Intracellular Ca²⁺ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration

by Raúl Lagos-Cabré, Marianne Brenet, Jorge Díaz, Ramón D. Pérez, Leonardo A. Pérez, Rodrigo Herrera-Molina, Andrew F. G. Quest and Lisette Leyton

Int. J. Mol. Sci. 2018, 19(8), 2179; https://doi.org/10.3390/ijms19082179 - 26 Jul 2018

Cited by 26 | Viewed by 5072

Abstract

Under pro-inflammatory conditions, astrocytes become reactive and acquire a migratory phenotype. Our results show that hemichannels formed by connexin 43 (Cx43) play an important role in Thy-1-induced astrocyte migration. The neuronal protein Thy-1 binds to αvβ3 integrin in astrocytes, thereby leading to intricate [...] Read more.

Under pro-inflammatory conditions, astrocytes become reactive and acquire a migratory phenotype. Our results show that hemichannels formed by connexin 43 (Cx43) play an important role in Thy-1-induced astrocyte migration. The neuronal protein Thy-1 binds to αvβ3 integrin in astrocytes, thereby leading to intricate signaling pathways that include calcium (Ca²⁺) release from intracellular stores, opening of Cx43 hemichannels, release of ATP, activation of P2X7 receptor, and Ca²⁺ influx. However, because these Thy-1 effects occur exclusively in reactive astrocytes, we wondered whether by elevating calcium levels and promoting hemichannel opening we could prompt non-reactive astrocytes to respond to Thy-1. Cx43 immunoreactivity increased at juxta-membrane sites, where hemichannels (not gap junctions) participate in astrocyte polarization and migration stimulated by Thy-1. Also, intracellular Ca²⁺ increase, due to ionomycin treatment, induced hemichannel opening, but activated astrocyte migration only partially, and this limitation was overcome by pre-treatment with tumor necrosis factor (TNF) and Thy-1. Finally, αvβ3 integrin formed membrane clusters after TNF stimulation or overexpression of β3 integrin. We suggest that these microclusters are required for cells to respond to Thy-1 stimulation. Therefore, the large increase in intracellular Ca²⁺ and hemichannel opening induced by ionomycin are required, but not sufficient, to permit Thy-1-induced astrocyte migration. Thus, we suggest that proinflammatory stimuli prompt astrocytes to respond to migratory signals of neuronal cells. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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19 pages, 19470 KiB

Open AccessArticle

Angiotensin II-Induced Mesangial Cell Damage Is Preceded by Cell Membrane Permeabilization Due to Upregulation of Non-Selective Channels

by Gonzalo I. Gómez, Paola Fernández, Victoria Velarde and Juan C. Sáez

Int. J. Mol. Sci. 2018, 19(4), 957; https://doi.org/10.3390/ijms19040957 - 23 Mar 2018

Cited by 15 | Viewed by 5532

Abstract

Connexin43 (Cx43), pannexin1 (Panx1) and P2X₇ receptor (P2X₇R) are expressed in kidneys and are known to constitute a feedforward mechanism leading to inflammation in other tissues. However, the possible functional relationship between these membrane channels and their role in damaged [...] Read more.

Connexin43 (Cx43), pannexin1 (Panx1) and P2X₇ receptor (P2X₇R) are expressed in kidneys and are known to constitute a feedforward mechanism leading to inflammation in other tissues. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remain unknown. In the present work, we found that MES-13 cells, from a cell line derived from mesangial cells, stimulated with angiotensin II (AngII) developed oxidative stress (OS, thiobarbituric acid reactive species (TBARS) and generated pro-inflammatory cytokines (ELISA; IL-1β and TNF-α). The membrane permeability increased progressively several hours before the latter outcome, which was a response prevented by Losartan, indicating the involvement of AT1 receptors. Western blot analysis showed that the amount of phosphorylated MYPT (a substrate of RhoA/ROCK) and Cx43 increased progressively and in parallel in cells treated with AngII, a response followed by an increase in the amount in Panx1 and P2X₇R. Greater membrane permeability was partially explained by opening of Cx43 hemichannels (Cx43 HCs) and Panx1 channels (Panx1 Chs), as well as P2X₇Rs activation by extracellular ATP, which was presumably released via Cx HCs and Panx1 Chs. Additionally, inhibition of RhoA/ROCK blocked the progressive increase in membrane permeability, and the remaining response was explained by the other non-selective channels. The rise of activity in the RhoA/ROCK-dependent pathway, as well as in Cx HCs, P2X₇R, and to a minor extent in Panx1 Chs led to higher amounts of TBARS and pro-inflammatory cytokines. We propose that AngII-induced mesangial cell damage could be effectively inhibited by concomitantly inhibiting the RhoA/ROCK-dependent pathway and one or more non-selective channel(s) activated through this pathway. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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17 pages, 8357 KiB

Open AccessArticle

TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

by Sara Crespo Yanguas, Tereza C. Da Silva, Isabel V. A. Pereira, Joost Willebrords, Michaël Maes, Marina Sayuri Nogueira, Inar Alves de Castro, Isabelle Leclercq, Guilherme R. Romualdo, Luís F. Barbisan, Luc Leybaert, Bruno Cogliati and Mathieu Vinken

Int. J. Mol. Sci. 2018, 19(3), 817; https://doi.org/10.3390/ijms19030817 - 12 Mar 2018

Cited by 32 | Viewed by 4688

Abstract

Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building [...] Read more.

Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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12 pages, 2123 KiB

Open AccessArticle

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

by Michela Pecoraro, Michele Ciccarelli, Antonella Fiordelisi, Guido Iaccarino, Aldo Pinto and Ada Popolo

Int. J. Mol. Sci. 2018, 19(3), 757; https://doi.org/10.3390/ijms19030757 - 7 Mar 2018

Cited by 23 | Viewed by 4214

Abstract

Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), [...] Read more.

Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial K_ATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p.) was administered 30 min before DOXO (10 mg/kg i.p.) in C57BL/6j female mice for 1–3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca²⁺-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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4830 KiB

Open AccessArticle

Immunohistochemical Characterization of Connexin43 Expression in a Mouse Model of Diabetic Retinopathy and in Human Donor Retinas

by Odunayo O. Mugisho, Colin R. Green, Jie Zhang, Nicolette Binz, Monica L. Acosta, Elizabeth Rakoczy and Ilva D. Rupenthal

Int. J. Mol. Sci. 2017, 18(12), 2567; https://doi.org/10.3390/ijms18122567 - 29 Nov 2017

Cited by 24 | Viewed by 5345

Abstract

Diabetic retinopathy (DR) develops due to hyperglycemia and inflammation-induced vascular disruptions in the retina with connexin43 expression patterns in the disease still debated. Here, the effects of hyperglycemia and inflammation on connexin43 expression in vitro in a mouse model of DR and in [...] Read more.

Diabetic retinopathy (DR) develops due to hyperglycemia and inflammation-induced vascular disruptions in the retina with connexin43 expression patterns in the disease still debated. Here, the effects of hyperglycemia and inflammation on connexin43 expression in vitro in a mouse model of DR and in human donor tissues were evaluated. Primary human retinal microvascular endothelial cells (hRMECs) were exposed to high glucose (HG; 25 mM) or pro-inflammatory cytokines IL-1β and TNF-α (10 ng/mL each) or both before assessing connexin43 expression. Additionally, connexin43, glial fibrillary acidic protein (GFAP), and plasmalemma vesicular associated protein (PLVAP) were labeled in wild-type (C57BL/6), Akita (diabetic), and Akimba (DR) mouse retinas. Finally, connexin43 and GFAP expression in donor retinas with confirmed DR was compared to age-matched controls. Co-application of HG and cytokines increased connexin43 expression in hRMECs in line with results seen in mice, with no significant difference in connexin43 or GFAP expression in Akita but higher expression in Akimba compared to wild-type mice. On PLVAP-positive vessels, connexin43 was higher in Akimba but unchanged in Akita compared to wild-type mice. Connexin43 expression appeared higher in donor retinas with confirmed DR compared to age-matched controls, similar to the distribution seen in Akimba mice and correlating with the in vitro results. Although connexin43 expression seems reduced in diabetes, hyperglycemia and inflammation present in the pathology of DR seem to increase connexin43 expression, suggesting a causal role of connexin43 channels in the disease progression. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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1941 KiB

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Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment

by Michela Pecoraro, Antonio Rodríguez-Sinovas, Stefania Marzocco, Michele Ciccarelli, Guido Iaccarino, Aldo Pinto and Ada Popolo

Int. J. Mol. Sci. 2017, 18(10), 2121; https://doi.org/10.3390/ijms18102121 - 11 Oct 2017

Cited by 38 | Viewed by 4879

Abstract

The use of Doxorubicin (DOXO), a potent antineoplastic agent, is limited by the development of cardiotoxicity. DOXO-induced cardiotoxicity is multifactorial, although alterations in calcium homeostasis, seem to be involved. Since even the Connexin43 (Cx43) plays a pivotal role in these two phenomena, in [...] Read more.

The use of Doxorubicin (DOXO), a potent antineoplastic agent, is limited by the development of cardiotoxicity. DOXO-induced cardiotoxicity is multifactorial, although alterations in calcium homeostasis, seem to be involved. Since even the Connexin43 (Cx43) plays a pivotal role in these two phenomena, in this study we have analyzed the effects of DOXO on Cx43 expression and localization. Damage caused by anthracyclines on cardiomyocytes is immediate after each injection, in the present study we used a short-term model of DOXO-induced cardiomyopathy. C57BL/6j female mice were randomly divided in groups and injected with DOXO (2 or 10 mg/kg i.p.) for 1–3 or 7 days once every other day. Cardiac function was assessed by Echocardiography. Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCAII) and phospholamban (PLB) expression were assessed by Western blot analysis, intracellular [Ca²⁺] were detected spectrofluorometrically by means of Fura-2 pentakis (acetoxymethyl) ester (FURA-2AM), and Cx43 and pCx43 expression and localization was analyzed by Western blot and confirmed by immunofluorescence analysis. DOXO induces impairment in Ca²⁺ homeostasis, already evident after a single administration, and affects Cx43 expression and localization. Our data suggest that DOXO-induced alterations in Ca²⁺ homeostasis causes in the cells the induction of compensatory mechanisms until a certain threshold, above which cardiac injury is triggered. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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Review

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23 pages, 1863 KiB

Open AccessReview

The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis

by Silvana Valdebenito, Emil Lou, John Baldoni, George Okafo and Eliseo Eugenin

Int. J. Mol. Sci. 2018, 19(5), 1270; https://doi.org/10.3390/ijms19051270 - 24 Apr 2018

Cited by 32 | Viewed by 7095

Abstract

Neoplastic growth and cellular differentiation are critical hallmarks of tumor development. It is well established that cell-to-cell communication between tumor cells and “normal” surrounding cells regulates tumor differentiation and proliferation, aggressiveness, and resistance to treatment. Nevertheless, the mechanisms that result in tumor growth [...] Read more.

Neoplastic growth and cellular differentiation are critical hallmarks of tumor development. It is well established that cell-to-cell communication between tumor cells and “normal” surrounding cells regulates tumor differentiation and proliferation, aggressiveness, and resistance to treatment. Nevertheless, the mechanisms that result in tumor growth and spread as well as the adaptation of healthy surrounding cells to the tumor environment are poorly understood. A major component of these communication systems is composed of connexin (Cx)-containing channels including gap junctions (GJs), tunneling nanotubes (TNTs), and hemichannels (HCs). There are hundreds of reports about the role of Cx-containing channels in the pathogenesis of cancer, and most of them demonstrate a downregulation of these proteins. Nonetheless, new data demonstrate that a localized communication via Cx-containing GJs, HCs, and TNTs plays a key role in tumor growth, differentiation, and resistance to therapies. Moreover, the type and downstream effects of signals communicated between the different populations of tumor cells are still unknown. However, new approaches such as artificial intelligence (AI) and machine learning (ML) could provide new insights into these signals communicated between connected cells. We propose that the identification and characterization of these new communication systems and their associated signaling could provide new targets to prevent or reduce the devastating consequences of cancer. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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15 pages, 1837 KiB

Open AccessReview

Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System

by Miaki Uzu, Wun Chey Sin, Ayaka Shimizu and Hiromi Sato

Int. J. Mol. Sci. 2018, 19(4), 1159; https://doi.org/10.3390/ijms19041159 - 11 Apr 2018

Cited by 23 | Viewed by 5596

Abstract

The tumor microenvironment is known to have increased levels of cytokines and metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around the tumor that responds to the inflammatory environment is likely to be subsequently altered. We [...] Read more.

The tumor microenvironment is known to have increased levels of cytokines and metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around the tumor that responds to the inflammatory environment is likely to be subsequently altered. We discuss how these abnormalities will support tumor survival via the actions of gap junctions (GJs) and hemichannels (HCs) which are composed of hexamer of connexin43 (Cx43) protein. In particular, we discuss how GJ intercellular communication (GJIC) in glioma cells, the primary brain tumor, is a regulatory factor and its attenuation leads to tumor invasion. In contrast, the astrocytes, which are normal cells around the glioma, are “hijacked” by tumor cells, either by receiving the transmission of malignant substances from the cancer cells via GJIC, or perhaps via astrocytic HC activity through the paracrine signaling which enable the delivery of these substances to the distal astrocytes. This astrocytic signaling would promote tumor expansion in the brain. In addition, brain metastasis from peripheral tissues has also been known to be facilitated by GJs formed between cerebral vascular endothelial cells and cancer cells. Astrocytes and microglia are generally thought to eliminate cancer cells at the blood–brain barrier. In contrast, some reports suggest they facilitate tumor progression as tumor cells take advantage of the normal functions of astrocytes that support the survival of the neurons by exchanging nutrients and metabolites. In summary, GJIC is essential for the normal physiological function of growth and allowing the diffusion of physiological substances. Therefore, whether GJIC is cancer promoting or suppressing may be dependent on what permeates through GJs, when it is active, and to which cells. The nature of GJs, which has been ambiguous in brain tumor progression, needs to be revisited and understood together with new findings on Cx proteins and HC activities. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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17 pages, 12742 KiB

Open AccessReview

The Potential for Connexin Hemichannels to Drive Breast Cancer Progression through Regulation of the Inflammatory Response

by J. Matthew Rhett and Elizabeth S. Yeh

Int. J. Mol. Sci. 2018, 19(4), 1043; https://doi.org/10.3390/ijms19041043 - 30 Mar 2018

Cited by 12 | Viewed by 4331

Abstract

Over the past few decades, connexin hemichannels have become recognized as major players in modulating the inflammatory response. Chronic inflammation is documented to promote tumorigenesis and is a critical component of tumor progression. Furthermore, inflammation is strongly linked to angiogenesis, immunotolerance, invasiveness, metastasis, [...] Read more.

Over the past few decades, connexin hemichannels have become recognized as major players in modulating the inflammatory response. Chronic inflammation is documented to promote tumorigenesis and is a critical component of tumor progression. Furthermore, inflammation is strongly linked to angiogenesis, immunotolerance, invasiveness, metastasis, and resistance in breast cancers. In this review, the literature on the role of connexin hemichannels in inflammation is summarized, and the potential role for hemichannel-mediated inflammation in driving breast cancer progression is discussed. Lastly, the potential for connexin-based therapeutics to modulate the inflammatory component of the tumor microenvironment as an avenue for the treatment of breast cancer is also discussed. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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26 pages, 732 KiB

Open AccessReview

Role of Non-Myocyte Gap Junctions and Connexin Hemichannels in Cardiovascular Health and Disease: Novel Therapeutic Targets?

by Robert D. Johnson and Patrizia Camelliti

Int. J. Mol. Sci. 2018, 19(3), 866; https://doi.org/10.3390/ijms19030866 - 15 Mar 2018

Cited by 49 | Viewed by 5650

Abstract

The heart is a complex organ composed of multiple cell types, including cardiomyocytes and different non-myocyte populations, all working closely together to determine the hearts properties and maintain normal cardiac function. Connexins are abundantly expressed proteins that form plasma membrane hemichannels and gap [...] Read more.

The heart is a complex organ composed of multiple cell types, including cardiomyocytes and different non-myocyte populations, all working closely together to determine the hearts properties and maintain normal cardiac function. Connexins are abundantly expressed proteins that form plasma membrane hemichannels and gap junctions between cells. Gap junctions are intracellular channels that allow for communication between cells, and in the heart they play a crucial role in cardiac conduction by coupling adjacent cardiomyocytes. Connexins are expressed in both cardiomyocytes and non-myocytes, including cardiac fibroblasts, endothelial cells, and macrophages. Non-myocytes are the largest population of cells in the heart, and therefore it is important to consider what roles connexins, hemichannels, and gap junctions play in these cell types. The aim of this review is to provide insight into connexin-based signalling in non-myocytes during health and disease, and highlight how targeting these proteins could lead to the development of novel therapies. We conclude that connexins in non-myocytes contribute to arrhythmias and adverse ventricular remodelling following myocardial infarction, and are associated with the initiation and development of atherosclerosis. Therefore, therapeutic interventions targeting these connexins represent an exciting new research avenue with great potential. Full article

(This article belongs to the Special Issue Involvement of Connexin Hemichannels in the Inflammatory Response of Chronic Diseases)

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