High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway.
Angiotensin II (Ang II), protein kinase C (PKC), reactive oxygen species (ROS) generated by NADPH oxidase, the activation of Janus kinase 2 (JAK2), and the polyol pathway play important parts in the hyperproliferation of vascular smooth muscle cells (VSMC), a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between the polyol pathway, PKC-beta, ROS, JAK2, and Ang II in the development of diabetic macroangiopathy. VSMC cultured in high glucose (HG; 25 mm) showed significant increases in the tyrosine phosphorylation of JAK2, production of ROS, and proliferation activities when compared with VSMC cultured in normal glucose (5.5 mm (NG)). Both the aldose reductase specific inhibitor (zopolrestat) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of JAK2, the production of ROS, and proliferation of VSMC induced by HG, but it had no effect on the Ang II-induced activation of these parameters in both NG and HG. However, transfection with PKC-beta antisense oligonucleotide, preincubation with a PKC-beta-specific inhibitor (LY379196) or apocynin (NADPH oxidase-specific inhibitor), or electroporation of NADPH oxidase antibodies blocked the Ang II-induced JAK2 phosphorylation, production of ROS, and proliferation of VSMC in both NG and HG. These observations suggest that the polyol pathway hyperactivity induced by HG contributes to the development of diabetic macroangiopathy through a PKC-beta-ROS activation of JAK2.
Shaw
Sean
S
Vascular Biology Center and the Institute of Molecular Medicine, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
Wang
Xiaodan
X
Redd
Heather
H
Alexander
Gwendolyn D
GD
Isales
Carlos M
CM
Marrero
Mario B
MB
D000098:Acetophenones / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D052160:Benzothiazoles; D002478:Cells, Cultured; D004357:Drug Synergism; D018274:Electroporation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000098:Acetophenones; D000906:Antibodies; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D010793:Phthalazines; D011108:Polymers; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014662:Vasoconstrictor Agents; C024617:polyol; D000804:Angiotensin II; C067172:zopolrestat; D014443:Tyrosine; C056165:acetovanillone; D000449:Aldehyde Reductase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat; D005947:Glucose