Remodeling of connexin 43 in the diabetic rat heart.
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.
Lin
Hai
H
Department of Physiology, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Ogawa
Koichi
K
Imanaga
Issei
I
Tribulova
Narcis
N
D000818:Animals; D002450:Cell Communication; D018031:Connexin 43 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004594:Electrophysiology; D017629:Gap Junctions / Q000378:metabolism*; D006321:Heart; D015151:Immunoblotting; D007150:Immunohistochemistry; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin
D018031:Connexin 43; D007976:Leupeptins; D020033:Protein Isoforms; C063261:acetylleucyl-leucyl-norleucinal; D013311:Streptozocin; D011493:Protein Kinase C; C032854:leupeptin