Connexin 43 expressed in endothelial cells modulates monocyte-endothelial adhesion by regulating cell adhesion proteins

Yuan, Ding; Sun, Guoliang; Zhang, Rui; Luo, Chenfang; Ge, Mian; Luo, Gangjian; Hei, Ziqing

doi:10.3892/mmr.2015.4273

Cited by 30 publications

(27 citation statements)

References 30 publications

(52 reference statements)

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“…In contrast, Cx43 has been associated with atherogenesis as it is highly expressed in atherosclerotic plaques compared to control (Kwak et al, 2002;Morel, 2014). Cx43 also has atherogenic properties as decreasing Cx43 expression reduces the formation of atherosclerotic lesions in vivo (Kwak et al, 2003;Wong et al, 2003;Wang et al, 2013b) while in vivo Cx43 upregulation increased the expression of cell adhesion proteins such as VCAM-1, thereby enhancing monocyte-endothelial adhesion, a key event in initiating atherosclerosis (Yuan et al, 2015). Furthermore, Cx43 has been implicated in endothelial cellular stiffness that is associated with cardiovascular disease and atherosclerosis (Okamoto et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

et al. 2020

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Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before. Materials and Methods: Telomerase-immortalized human Coronary Artery/ Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19). Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19. Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.

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Section: Introductionmentioning

confidence: 99%

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

et al. 2020

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“…BM endothelial cells (EC) line the interior of all blood vessels and regulate HSC expansion and the reconstitution of hematopoiesis after myeloablation [6,7,95,118]. EC expresses Cx37, Cx40, Cx43, and Cx45, which contribute to the regulation of blood flow, leukocyte adhesion and extravasation, vasomotor activity, angiogenesis, and the functional maintenance of vasculature [119,120]. The GJ protein, Cx43 is the major connexin expressed by EC and maintains the normal vascular function, and EC specific deletion of Cx43 in mice (EC-Cx43 ∆/∆ mice) results in hypotension, bradycardia, and compensatory hyperreninemia and hyperangiotensinemia [121].…”

Section: Endothelial Cellsmentioning

confidence: 99%

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

Singh

Cancelas

2020

IJMS

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The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.

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“…In contrast to the atheroprotective effects of Cx37 and Cx40, Cx43 has been suggested to be pro-atherosclerotic. Indeed, downregulation of Cx43 expression inhibited monocyte-endothelial adhesion by decreasing the expression levels of cell adhesion proteins, whereas its upregulation enhanced the adhesion of monocytes to endothelial cells [159]. Besides their roles in atherosclerosis, Cxs were reported to be highly sensitive to ionizing radiation [156].…”

Section: Intercellular Communicationmentioning

confidence: 99%

Selected Endothelial Responses after Ionizing Radiation Exposure

Baselet¹,

Ramadan²,

MohammedBenotmane³

et al. 2018

Endothelial Dysfunction - Old Concepts and New Challenges

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Along with the development of novel chemotherapeutic agents, radiation therapy has revolutionized the prognosis of patients with various cancers. However, with a longer life expectancy, radiation treatment-related comorbidity, like cardiovascular diseases (CVDs), becomes an issue for cancer survivors. In addition, exposure to X-rays for medical diagnostics is dramatically increasing at the present times. A pressing question is whether or not exposure to these very low doses can cause health damage. Below 0.5 gray (Gy), an increased risk cannot be evidenced by epidemiology alone, and in vitro and in vivo mechanistic studies focused on the elucidation of molecular signaling pathways are needed. Given the critical role of the endothelium in normal vascular functions, a complete understanding of radiation-induced endothelial dysfunction is crucial. In this way, the current radiation protection system could be refined if needed, making it possible to more accurately assess the cardiovascular risk in the low-dose region. Finally, radiation-induced CVD, like CVD in general, is a progressive disorder that may take years to decades to manifest. Therefore, experimental studies are warranted to fulfill the urgent need to identify noninvasive biomarkers for an early detection and potential interventions-together with a healthy lifestyle-that may prevent or mitigate these adverse effects.

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Connexin 43 expressed in endothelial cells modulates monocyte-endothelial adhesion by regulating cell adhesion proteins

Cited by 30 publications

References 30 publications

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

Selected Endothelial Responses after Ionizing Radiation Exposure

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