| Research Abstract |
Functional regulation of gap junction which essentially contributes to intercellular impulse propagation depends on phosphorylation of connexin composing the gap junction channel. 2 main factors of phosphorylation are intracellular signal of PKA and PKC. In this study, Remodeling of connexin 43 (Cx43) by PKA or PKC and relationship the remodeling of Cx43 and susceptibility of the heart to arrhythmias (aconitine-induced ventricular fibrillation) were examined on isolated rat or guinea-pig hearts using methods of electrophysiology, immunoblot and immunohistochemistry.
In the PMA treated heart, the diabetic heart (STZ-induced rat : Type I, OLETF, GK rat : TypeII), an acceleration of activity of PKC ε, an augmentation of the PKC ε-mediated phosphorylation of Cx43 and a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area, an increase in ventricular tissue Angiotensin II (AngII) level were observed in association with electrical cell-to-cell decoupli
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ng. These downward remodeling of Cx43 were ameliorated by PKC inhibitors, Proteasomal inhibitors or Lysosomal inhibitors. In the hypoxic heart, a reduction of the PKA-mediated phosphorylation, a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area were observed in association of electrical cell-to-cell decoupling. These downward remodeling of Cx43 ware restored by PKA activators.
On the mechanism of generation of tachyarrhythmias, such as, ventricular fibrillation (VF), both acceleration of automatic activity and electrical interaction between neighboring cells (microreentry) caused by disturbances of the gap junction are essentially involved. In this meanings, dysfunction of the gap junction contributes to generation of the cardiac fibrillation. After application of aconitine, the electrical fluttering activity was spontaneously followed by VF. At the beginning of VF, an acceleration of activity of PKC ε, a reduction of the PKA-mediated phosphorylation, an augmentation of PKC ε- mediated phosphorylation of Cx43 and a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area, an increase in ventricular tissue AngII level were observed with irregular interaction of electrical activity between neighboring cells. These changes were promoted as VF advanced.
In the diabetic heart (Type I, II), the PMA-treated or the Ang. II analog-treated heart, susceptibility to VF was remarkably augmented. These effects were abolished by PKC inhibitors, Ang. II receptor antagonists or proteolytic inhibitors. In the hypoxic heart, also, generation of fibrillation was accelerated. On the other hand, PKA activators cyclic AMP analog prevented the initiation of W with an increase in quantity and expression of Cx43.
It is concluded that the downward remodeling of Cx43 contributes to generation of VF forming substrate for reentry. The downward remodeling of Cx43 is induced by the PKC E-mediated hyperphosphorylation and dephosphorylation of the PKA-mediated residue of Cx43, and is promoted by VF itself. It is suggested that in clinical implication, PKA activators, PKC inhibitors or Ang II blockers prevent or ihibit generation of VF. Less
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