The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43

Clarke, Thomas C.; Thomas, Dafydd G.; Petersen, Jørgen S.; Evans, William Howard; Martin, Patricia

doi:10.1038/sj.bjp.0706631

Cited by 63 publications

(50 citation statements)

References 42 publications

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“…Rotigaptide augmented gap-junctional conductance and improved cell coupling (Shiroshita-Takeshita et al, 2007). Rotigaptide also increased coupling in cells expressing Cx43, but not those expressing Cx32 and Cx26 (Clarke et al, 2006).…”

Section: Peptides As Therapeutic Toolsmentioning

confidence: 96%

Mimetic Peptides as Blockers of Connexin Channel-Facilitated Intercellular Communication

Evans

Leybaert

2007

Cell Communication & Adhesion

136

106

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Section: Peptides As Therapeutic Toolsmentioning

confidence: 96%

Mimetic Peptides as Blockers of Connexin Channel-Facilitated Intercellular Communication

Evans

Leybaert

2007

Cell Communication & Adhesion

136

106

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“…It would be easy to determine the extent of myocardial salvage by GJC inhibition if there were a specific and direct opener of closed gap junctions. A new gap junction opener, rotigaptide (4,11,35), is apparently selective. However, it suppresses the dephosphorylation of Ser297 and Ser368 in Cx43 during ischemia, indicating the activation of a protein kinase and/or the inhibition of a PP.…”

Section: Ipc-induced Suppression Of Chemical Gjc During Ischemia and mentioning

confidence: 99%

Role of the gap junction in ischemic preconditioning in the heart

Miura

Miki

Yano

2010

American Journal of Physiology-Heart and Circulatory Physiology

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The gap junction plays roles not only in electrical coupling of cardiomyocytes but also in intercellular transport of biologically active substances. Furthermore, the gap junction participates in decision making on cell survival versus cell death in various types of cells, and a part of reperfusion injury in the heart has been indicated to be gap junction mediated. The contribution of gap junction communication (GJC) and/or mitochondrial "hemichannels" to protective signaling during the trigger phase of ischemic preconditioning (IPC) is suggested by observations that IPC failed to protect the heart when GJC was blocked during IPC. Although ischemia suppresses both electrical and chemical GJC, chemical GJC persists for a considerable time after electrical GJC is lost. IPC facilitates the ischemia-induced suppression of chemical GJC, whereas IPC delays the reduction of electrical GJC after ischemia. The inhibition of GJC during sustained ischemia and reperfusion by GJC blockers mimics the effect of IPC on myocardial necrosis. IPC induces distinct effects on the interaction of connexin-43 with protein kinases, and the phosphorylation of connexin-43 at Ser368 by PKCepsilon is a primary mechanism of inhibition of chemical GJC by IPC. Several lines of evidence support the notion that the modulation of GJC is a part of the mechanism of IPC-induced protection against myocardial necrosis and arrhythmias, though what percentage of IPC protection is attributable to the inhibition of GJC during ischemia-reperfusion still remains unclear.

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“…27 However, another study failed to observe changes in the phosphorylation status of connexin 43 in response to rotigaptide. 28 Rotigaptide increases connexin 43 expression after 24 hours in neonatal rat cardiomyocytes, 29 but such an effect is unlikely to explain changes after short-term intravenous administration.…”

Section: Relation To Previous Observations On the Effects Of Antiarrhmentioning

confidence: 99%

Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

et al. 2007

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Background-Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction-enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia. Methods and Results-Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (Pϭ0.003) and increased AF duration (Pϭ0.008), with AF lasting Ͼ3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (Pϭ0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (Pϭ0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemiainduced conduction slowing and AF duration increases. Conclusions-Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates. (Circulation. 2007;115:310-318.)

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The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43

Cited by 63 publications

References 42 publications

Mimetic Peptides as Blockers of Connexin Channel-Facilitated Intercellular Communication

Mimetic Peptides as Blockers of Connexin Channel-Facilitated Intercellular Communication

Role of the gap junction in ischemic preconditioning in the heart

Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

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