A Peptide Mimetic of the Connexin43 Carboxyl Terminus Reduces Gap Junction Remodeling and Induced Arrhythmia Following Ventricular Injury

作者：O'Quinn Michael P; Palatinus Joseph A; Harris Brett S; Hewett Kenneth W; Gourdie Robert G^*

来源：Circulation Research, 2011, 108(6): 704-715.

DOI：10.1161/CIRCRESAHA.110.235747

• arrhythmia
• intercalated disks
• gap junction remodeling
• Cx43
• ZO-1

Rationale: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia.
Objectives: A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ)-binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic alpha CT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether alpha CT1 affected arrhythmic propensity; and (3) the mechanism of alpha CT1 effects on arrhythmogenicity and GJ remodeling.
Methods and Results: A cryoinjury model generating a reproducible wound and injury border zone (IBZ) in the LV was used. Adherent methylcellulose patches formulated to locally release alpha CT1 (< 48 hours) were placed on cryoinjuries. Relative to controls, Cx43/ZO-1 colocalization in the IBZ was reduced by alpha CT1 by 24 hours after injury. Programmed electric stimulation ex vivo and optical mapping of voltage transients indicated that peptide-treated hearts showed reduced inducible arrhythmias and increased ventricular depolarization rates 7 to 9 days after injury. At 24 hours and 1 week after injury, alpha CT1-treated hearts maintained Cx43 in intercalated disks (IDs) in the IBZ, whereas by 1 week after injury, controls demonstrated Cx43 remodeling from IDs to lateralized distributions. Over a postinjury time course of 1 week, alpha CT1-treated IBZs showed increased Cx43 phosphorylation at serine368 (Cx43-pS368) relative to control tissues. In biochemical assays, alpha CT1 promoted phosphorylation of serine368 by protein kinase (PK) C-epsilon in a dose-dependent manner that was modulated by, but did not require ZO-1 PDZ2.
Conclusions: alpha CT1 increases Cx43-pS368 in vitro in a PKC-epsilon-dependent manner and in the IBZ in vivo acutely following ventricular injury. alpha CT1-mediated increase in Cx43-pS368 phosphorylation may contribute to reductions in inducible-arrhythmia following injury. (Circ Res. 2011;108:704-715.)

• 出版日期2011-3-18