Altered gap junction activity in cardiovascular tissues of diabetes.
Hyperglycemia appears to be an important etiologic factor in the development of micro- and macrovascular complications in diabetic patients. However, its detailed molecular mechanism remains unclear. Among various possible mechanisms, it is widely accepted that high glucose level and a diabetic state induce protein kinase C (PKC) activation in vascular cells in cultured and vascular tissues of diabetic animals. Gap junctions are clusters of membrane channels that permit the intercellular exchange of ions and second messengers between adjacent cells. Gap junctional intercellular communication (GJIC) plays an important role in cardiovascular tissue homeostasis. Here we report that GJIC in cultured vascular cells such as endothelial cells and smooth muscle cells is inhibited by high glucose level. Furthermore, we show that it is mediated by PKC-dependent excessive phosphorylation of connexin-43 which is the main functional component of gap junction in vascular cells. In addition, we also show that in diabetic rats, PKC-dependent excessive phosphorylation of connexin-43 induces the impairment of ventricular conduction in the heart. These results suggest that PKC-dependent impairment of GJIC may lead to various disorders of cardiovascular homeostasis and contribute to cardiovascular dysfunctions associated with diabetes.
Inoguchi
T
T
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. toyoshi@intmed3.med.kyushu-u.ac.jp
Yu
H Y
HY
Imamura
M
M
Kakimoto
M
M
Kuroki
T
T
Maruyama
T
T
Nawata
H
H
D000818:Animals; D002319:Cardiovascular System / Q000503:physiopathology*; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004553:Electric Conductivity; D004789:Enzyme Activation; D017629:Gap Junctions / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats
D018031:Connexin 43; D011493:Protein Kinase C; D005947:Glucose