Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Wang, Xuehui; Zhuo, Xianlu; Ni, Yajuan; Gong, Min; Wang, Tingzhong; Lu, Qun; Ma, Aiqun

doi:10.3724/sp.j.1263.2012.03271

Cited by 22 publications

(7 citation statements)

References 40 publications

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“…For Cx43 such states are reported [66]. More, the conditional state of Cx43 is reported to be under control of neuregulin-1β in cardiac myocytes, thus a similar situation in the experiments presented here must be regarded [67]. In addition, connexins not organized in gap junctions address physiological functions [68], and the functional capability of connexins is rather unspecific in that gap junction introduced as xenografts can be of functionality in the non-canonical acceptor cell [69].…”

Section: Discussionsupporting

confidence: 56%

Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy

Pilarczyk

Papenfuß

Bestvater

et al. 2019

Cancers

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Cancer studies suggest that the spatial localization of connexin43 (Cx43) could play an important role during tumor genesis and the formation of metastasis. Cx43 has been shown to be upregulated in cancer cells; thereby a shift from Cx43 normal localization in gap junctions in the cell membrane towards a primarily cytoplasmic localization was observed in many studies. So far neither the spatial arrangements of Cx43 in breast cancer cells nor the effects of treatment outcome (ionizing radiation and antibody therapy) on the spatial arrangements of Cx43, have been microscopically studied on the nanoscale. This has brought up the idea to study the micro- and nanoscaled spatial Cx43 arrangements in a model of breast cancer-related cell types, i.e., SkBr3 breast cancer cells, BJ fibroblasts, and primary human internal mammary artery endothelial cells (HIMAECs). The cells were treated with neuregulin1 (NRG1), trastuzumab (Herceptin), or 6MeV-photon irradiation at a dose of 4 Gy. NRG1 stimulates further NRG1 release in the tumor endothelium that may lead to an enhanced tumor protective effect whereas Herceptin, used in antibody treatment, works in an antagonistic fashion to NRG1. After fluorescent labelling with specific antibodies, the molecular positions of Cx43 in the perinuclear cytosol and in the cell periphery at the membrane were determined for the three treatment related applications (NRG1, trastuzumab, 4 Gy irradiation) using confocal laser scanning microscopy (CLSM) and single molecule localization microscopy (SMLM). These techniques enable investigations of Cx43 enrichment and topological arrangements of Cx43 molecules from the micro-scale of a whole cell to the nano-scale of single molecules. In SkBr3 cells with and without radiation treatment high density accumulations were detected which seem to be diluted after NRG1 and trastuzumab treatment although the SMLM distance frequency distributions did not significantly vary. In BJ fibroblasts and HIMAECs differences between periphery and perinuclear cytosol were observed after the different treatment processes. HIMAECs showed significant Cx43 accumulation after NRG1, trastuzumab, and radiation treatment in the perinuclear region whereas in the periphery radiation has less influence as compared to the control. BJ cells were reacting to the treatments by Cx43 accumulations in the perinuclear region but also in the periphery. In conclusion, it was shown that by using CLSM and super-resolution SMLM, treatment effects on the spatial and thus functional arrangements of Cx43 became detectable for investigations of tumor response mechanisms.

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Section: Discussionsupporting

confidence: 56%

Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy

Pilarczyk

Papenfuß

Bestvater

et al. 2019

Cancers

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“…These changes in reduced Cx-43 expression and phosphorylation were associated with increased QTc. Recent study shown the role of neuroglin-1β in restoring Cx-43 and reduction in QTc in a ACF induced VO [50]. These changes can also result in diminished propagation of Ca 2+ waves [49] and may underlie reduced contractility and abrogated β-AR responsiveness seen in VO HF.…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

Guggilam

Hutchinson

West

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…In failing animal hearts, total Cx43 expression (Ai & Pogwizd, 2005; Danielson et al, 2013; Givvimani et al, 2014; Wang et al, 2012b) and Cx43 expression at gap junctions is reduced (Hesketh et al, 2010; Petrich et al, 2004; Wang et al, 2012b; Zhong et al, 2007) independent of the cause of heart failure. Similarly, in tissue samples from failing human hearts (dilated or ischemic cardiomyopathy), Cx43 expression is reduced and Cx43 is redistributed away from the gap junctions (Dupont et al, 2001; Kostin et al, 2003).…”

Section: Cx43 Function In the Presence Of Major Cardiovascular Rismentioning

confidence: 99%

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

Schulz

Görge

Görbe

et al. 2015

Pharmacology & Therapeutics

202

174

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Connexins are widely distributed proteins in the body that are crucially important for heart and brain function. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localisation at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodelling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injury as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissue following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.

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Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Cited by 22 publications

References 40 publications

Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy

Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy

In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

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