Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

Luo, Baoming; Yan, Yifei; Zeng, Zhiyu; Zhengnan, Zhang; Liu, Haide; Líu, Hao; Li, Jinyi; Huang, Weiqiang; Wu, Jiangtao; He, Yan

doi:10.3892/ijmm.2018.3648

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…In contrast, Alesutan et al demonstrated inhibition of Cx43 by AMPK (Alesutan et al, 2015); thus Cx43 and its interaction with AMPK in the context of electrical remodeling remains inconclusive. Furthermore, downregulation of Cx43 would lead to reduced EP coupling between atrial myocytes, which in turn would slow conduction velocity and increase AF susceptibility in atrial tissue (Luo et al, 2018). While we did not demonstrate a change in conduction velocity between groups there was a trend towards conduction lengthening in the vehicle treatment group.…”

Section: Stcontrasting

confidence: 62%

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

et al. 2021

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Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR.Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis.Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13.Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study.

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Section: Stcontrasting

confidence: 62%

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

et al. 2021

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“…In the process of myocardial ischemia or myocardial injury and fibrosis, the expression of Cx43 will decrease, resulting in electrophysiological remodeling of cardiomyocytes at the molecular level, leading to arrhythmia [ 25 , 26 ]. Moreover, the study has revealed that Cx43 reduces susceptibility to sympathetic atrial fibrillation [ 27 ]. In this study, it was found that after overexpression of SHP-1, the expression of Cx43 was significantly increased, indicating that SHP-1 can reduce myocardial fibrosis and effectively protect myocardial function.…”

Section: Discussionmentioning

confidence: 99%

Src-homology domain 2 containing protein tyrosine phosphatase-1 (SHP-1) directly binds to proto-oncogene tyrosine-protein kinase Src (c-Src) and promotes the transcriptional activation of connexin 43 (Cx43)

et al. 2022

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The prevalence of atrial fibrillation (AF), which is one of the common arrhythmias in clinics, is increasing sharply and has affected millions of patients, which is expected to triple by 2050. The purpose of the study was to explore the regulatory relationship between Src-homology domain 2 containing protein tyrosine phosphatase-1 (SHP-1) and proto-oncogene tyrosine-protein kinase Src (c-Src) and the regulation of Connexins 43 (Cx43), and its effect on AF was also studied. Mouse atrial myocyte line (HL-1 cell line) was used as the research object. After overexpression of SHP-1, the expressions of p-c-Src, Cx43, and SHP-1 were detected by Western blot and cellular immunofluorescence, respectively. The location and interaction of SHP-1 and c-Src in the cells were detected by immunofluorescence co-localization and co-immunoprecipitation (Co-IP). The regulation of c-Src and Cx43 was detected by DNA pull down, chromatin co-immunoprecipitation (CHIP), and dual-luciferase reporter system. The results revealed that overexpression of SHP-1 could inhibit the phosphorylation and activation of c-Src and increase the expression of Cx43. Moreover, there was a direct binding between SHP-1 and c-Src, and c-Src could bind to the promoter region of Cx43 and inhibit the transcription of Cx43. In conclusion, SHP-1 could bind to c-Src and inhibit the activity of c-Src, thus enhancing the transcriptional activation of Cx43 and improving the function of gap junction.

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“…In a sheep coronary infarct model, Cx43 was redistributed from the intercalated discs to the lateral surface, increasing fibroblast-cardiomyocyte coupling and resulting in an increased associated AF risk, likely due to impaired signal transduction between myocytes [134,135]. Another study showed Cx43 mediates the induction and maintenance of AF in a canine model [136]. Connexins can be regulated through phosphorylation by multiple kinases like CaMKII, PKA or PKC [137][138][139].…”

Section: Oxidative Stress and Inflammationmentioning

confidence: 99%

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

Beneke

Molina

2021

Hearts

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Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase with the aging of the population and many important fundamental and translational underlaying mechanisms remain elusive. Here, we review recent advances in molecular and cellular basis for AF initiation, maintenance and progression. We first provide an overview of the basic molecular and electrophysiological mechanisms that lead and characterize AF. Next, we discuss the upstream regulatory factors conducting the underlying mechanisms which drive electrical and structural AF-associated remodeling, including genetic factors (risk variants associated to AF as transcriptional regulators and genetic changes associated to AF), neurohormonal regulation (i.e., cAMP) and oxidative stress imbalance (cGMP and mitochondrial dysfunction). Finally, we discuss the potential therapeutic implications of those findings, the knowledge gaps and consider future approaches to improve clinical management.

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Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

Cited by 4 publications

References 36 publications

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

Src-homology domain 2 containing protein tyrosine phosphatase-1 (SHP-1) directly binds to proto-oncogene tyrosine-protein kinase Src (c-Src) and promotes the transcriptional activation of connexin 43 (Cx43)

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

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