Pannexin-1 channels and their emerging functions in cardiovascular diseases

Li, Lanfang; He, Lu; Wu, Di; Jiang, Zhisheng

doi:10.1093/abbs/gmv028

Cited by 24 publications

(22 citation statements)

References 95 publications

(96 reference statements)

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“…Besides Cx43 hemichannels, pannexin-1 channels are also involved in cardiac fibrosis formation, likely via release of ATP from the cardiomyocytes (Nishida et al, 2008;Kar et al, 2012;Li et al, 2015). Pannexin-1 can be activated by Ca 2+ released from the SR and allow passage of Ca 2+ , ATP and other small molecules across the membrane, in a manner similar to that of Cx43 hemichannels (Figure 3) (Li et al, 2015;Xu et al, 2018). Oxidative stress activates Pannexin-1 hemichannels and does increase ATP release of cardiomyocytes via Pannexin-1 (Zhang et al, 2008;Dolmatova et al, 2012).…”

Section: Ros-induced Fibroblast Differentiation In Acmmentioning

confidence: 99%

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.

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Section: Ros-induced Fibroblast Differentiation In Acmmentioning

confidence: 99%

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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“…Induced ischemia rapidly increases the glycosylation of Pannexin-1 and increases its trafficking to the plasma membrane. ATP release through Pannexin-1 channels is involved in cardiac fibrosis following myocardial infarction [ 10 ]. Bao et al demonstrated that Panx-1 hemichannels provides the ligand for the adenosine A2A receptors that plays a role in the inhibitory signal at the back of the neutrophil, and inhibition of Panx-1 hemichannels blocked A2A receptor stimulation preventing cAMP accumulation and impairing migration and polarization of neutrophils [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin

et al. 2017

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BackgroundFibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.MethodsThioacetamide (100mg/kg IP)-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5–10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5–10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.ResultsTreatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.ConclusionsThese studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.

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“…Panx1 has also been implicated in prevalent human pathologies including [ 1 4 _ T D $ D I F F ] ischemia, metabolic disease, and inflammation, making it a promising novel target for intervention [121]. However, the targeting of pannexins in therapeutics remains in its infancy, owing in large part to their more recent discovery.…”

Section: Connexin and Pannexin Therapeuticsmentioning

confidence: 99%