br During cardiac ischaemia a

During cardiac ischaemia, a decrease in GJ coupling is observed, which results in slower conduction of electrical impulses and a higher risk of arrhythmias.[13], [20] In Huntington’s disease an increase in the nourseothricin of 5 Cxs was observed in the astrocytes in the brain, suggesting an adaptive protective response. Cerebral ischaemia results in uncoupling of astrocytes due to a decrease in GJ function, which prevents astrocytes from being able to redistribute ions and neurotransmitters resulting in “cell swelling”. In cirrhosis and acute-on-chronic liver failure (ACLF), studies indicated that increased expression of hepatic Cx43 was related to the severity of inflammation. This was suggested to be an adaptive response of the liver for protection through better intercellular communication. Results on the role of Cx and GJ alterations during various pathological states are controversial (reviewed by). However, the ability of GJ proteins to participate in different physiological and pathological states makes them attractive therapeutic targets in different diseases. Therefore, this paper will review recent knowledge concerning the role of GJs in the pathogenesis of liver diseases.
Modulators of GJ function and targeting in diseases outside the liver Opposing approaches aimed at increasing or decreasing GJ function have been explored to treat different diseases. To improve GJ function in heart diseases, GJ openers, such as the synthetic peptides rotigaptide and danegaptide, were tested and shown to reduce the burden of arrhythmias and myocardial infarct size. However, a recently published phase II study did not confirm the early results. Other enhancers of GJ function such as ACT1, a peptide that mimics the carboxyl terminus of Cx43, have been evaluated in cutaneous ulcers and arrhythmias, where they led to wound re-epithelialization and reduced inducible arrhythmias following ventricular injury, respectively. Conversely, strategies that target specific Cxs with antisense oligonucleotide and mimetic peptides can be used if the goal is to block intercellular communication. These strategies have been shown to reduce inflammation and improve neuronal survival after cerebral and retinal ischaemia. They have also been shown to promote wound healing.[32], [33] In addition to the direct beneficial effects of simply potentiating or blocking the channel, the Cx targeting drugs may be used as adjuvants potentiating the effects of other known therapeutic agents. This is of particular interest in hepatocellular carcinoma (HCC) where GJs may favour the delivery of cytotoxic drugs to tumour cells. In this regard, studies have shown that GJ mimetics facilitate the spread of cisplatin, conferring a better therapeutic effect. Quinolone, a GJ opener was recently shown to enhance cisplatin-induced cytotoxicity, supporting the rationale for combination therapies that include GJ openers in the treatment of various cancers such as colon, prostate and breast. In addition, inhibition of GJ may reduce the toxic effects of drugs by preventing the propagation of inflammatory or death stimuli to neighbouring cells. Given the potentially opposing effects of modulating GJ function, clinical application in a given disease needs to be carefully considered.
Acute liver injury and inflammation GJs and Cxs are involved in settings where homeostatic regulation is crucial, such as during inflammation and cell death. Available data indicate that Cx26, Cx32 and Cx43 can contribute to acute liver injury and inflammation related to drugs, lipopolysaccharide (LPS) and ischaemia-reperfusion injury. Given that several immune cells including monocytes, macrophages and Kupffer cells express Cx43 and are known to be involved in autoimmune liver diseases, the role of GJs in specific autoimmune liver diseases should be explored.
Role of connexins in hepatic fibrosis In the normal liver, fenestrated liver sinusoidal endothelial cells induce senescence of hepatic stellate cells. Capillarization of sinusoids reduces the ability of endothelial cells to suppress stellate cell activity.[77], [78] Although GJs may provide a direct pathway of intercellular communication, functional communication between endothelial cells and stellate cells has yet to be consistently identified.[7], [79] However, as previously discussed, Cxs may contribute to intercellular transfer of angiocrine signals after injury or may be incorporated into microvesicles involved in promoting fibrogenesis. In this regard, Cxs, in particular Cx43, have been shown to contribute to the composition of membrane vesicles, making this an important target for future research.