Remodeling of connexin 43 in the diabetic rat heart

Abstract

In the Streptozotocin-induced diabetic rat heart, a decrease in the conductivity and suppression of electrical cell-to-cell coupling were observed. To clarify this mechanism, the present study was performed to investigate alterations of the gap junction connexin 43 (Cx43) using immunoblotting, immunohistochemistry, electron-microscopic analyses. An enhanced activation of PKCepsilon, an augmentation of PKCepsilon-mediated phosphorylation of Cx43, a decrease in the total amount of Cx43, a reduction in the area of immunoreactive particles for Cx43 at the intercalated disk, distribution of Cx43 to cell periphery or cytoplasm and the internalization approximately annular profiles of the gap junction were all characteristically recognized in the diabetic heart. Such abnormalities in the expression of Cx43 were alleviated by treatment with either lysosomal (NH(4)Cl, Leupeptin) or proteasomal inhibitor (ALLN). These results suggest that the PKCepsilon-mediated hyperphosphorylation of Cx43 makes Cx43 vulnerable to proteolytic degradation and that a decrease in the conductivity in the diabetic heart is also caused by a decrease in the number of gap junction channels due to an acceleration of the proteolytic degradation of Cx43. The remodeling of Cx43 induced by the activation of PKCepsilon may therefore contribute to the formation of the arrhythmogenic substrate in the diabetic heart. The cardioprotective effect of the remodeling of Cx43 by PKCepsilon is discussed.

The Effects of 2-Aminoethoxydiphenyl Borate and Diphenylboronic Anhydride on Gap Junctions Composed of Connexin43 in TM4 Sertoli Cells

“…The present study did not observe the increase in Cx43 amount after treatment with these inhibitors, which were proved in other studies. 39,40) We suppose the discrepancy with our results possibly due to differences in cell type or cell culture conditions, or a short treatment time, for that some reports demonstrated that treatment with Leu or ALLN for 5 h was not sufficient to increase intracellular Cx43 amount. 43,44) The mechanisms underlying the increase in Cx43 degradation induced by 2-APB and DPBA are unknown.…”

“…37,38) To delineate the degradation site of Cx43 induced by 2-APB and DPBA, cells were treated with the two agents and specific inhibitors of the lysosomal and proteasomal pathways for 4 h. Leupeptin (Leu), a potent lysosomal inhibitor, is widely used in the study of Cx43 degradation. 39,40) Proteasomal proteolysis is inhibited by ALLN, which is highly specific for the proteasomal pathway. 41) As shown in Fig.…”

Ultrastructure Changes of Cardiac Lymphatics During Cardiac Fibrosis in Hypertensive Rats

“…Connexin43 is a type of gap junction protein, which is found in the intercalated disk of the myocardium. It is associated with the transfer of impulses between adjacent cardiac muscles (Lin et al, 2006;Kostin, 2007). In our study, we found a decrease in expression of connexin43 in the Dahl S group when compared with the Dahl R group, which indicated that impulse transfer was impeded.…”

Myocardial connexin-43 and PKC signalling are involved in adaptation of the heart to irradiation-induced injury: Implication of miR-1 and miR-21

“…Enhanced phosphorylation of Cx43 may be in part attributed to increased expression of PKCε. Our previous studies suggest that enhanced Cx43 phosphorylation due to activation of PKCε was linked with slowing of myocardial conduction and decreasing susceptibility of diabetic or hypothyroid rat hearts to malignant arrhythmias (Lin et al 2006(Lin et al , 2008Bacova et al 2013). In contrast, reduced expression of PKCε accompanied by decreased Cx43 phosphorylation in hyperthyroid rat hearts was highly proarrhythmic .…”