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- Title
Hyperglycemia and IL-1 Beta-Induced INOS Overexpression via P38 MAPK in GK Diabetic Rat VSMC.
- Authors
Lee, Jin Hee; Xia, Shichao; Ragolia, Louis
- Abstract
Diabetes and atherosclerosis are accompanied by an increased inflammatory response due to vascular injury. The expression of pro-inflammatory cytokines, including IL-1beta, is up-regulated in animal models of, and patients with, type 2 diabetes. Inducible nitric oxide synthase (iNOS) has been demonstrated to be closely related to insulin resistance. However, the mechanism of how inflammation causes insulin resistance via iNOS overexpression has not been well established. Basal iNOS mRNA expression in Goto Kakizaki (GK) diabetic vascular smooth muscle cells (VSMC) is 4.4-fold higher than that of Wistar Kyoto (WKY) controls, as determined by real-time PCR. IL-1beta increased iNOS mRNA level to 8.6-fold higher than basal levels in GK VSMC compared to only a 2.9-fold increase in WKY VSMC. The NOS inhibitor, LNMMA, decreased IL-1beta-induced iNOS mRNA in both GK and WKY. Basal iNOS mRNA expression stimulated by high glucose (HG; 20mM) was higher than that of low glucose (LG; 5mM), implying that an increase in basal iNOS expression in diabetic GK is partly related to hyperglycemia. Basal iNOS protein expression was more than 6-fold higher in GK VSMC than WKY VSMC. IL-1beta increased iNOS to 6.8-fold in GK VSMC, while in WKY VSMC there was only 2.3-fold increase over control. HG stimulation reduced the expression of iNOS in WKYVSMC, while it caused an increase in GK VSMC. The p38 MAP Kinase (MAPK) specific inhibitor, SB203580, further increased the IL-1beta-stimulated iNOS expression both in WKY and GK VSMC. Interestingly, knock down of p38 MAPK also knocked down the iNOS expression in both VSMC, demonstrating the critical role of p38 MAPK on iNOS overexpression. Immunofluorescent labeling of frozen aorta sections was performed to determine whether the iNOS overexpression could be found in intact tissue. iNOS was expressed in the aorta medial layer in GK, but not in WKY, confirming iNOS overexpression in GK diabetic aorta. It appears iNOS may be induced by hyperglycemia and increased inflammation and play an important role in the pathophysiology of cardiovascular abnormalities in type 2 diabetes.
- Publication
Diabetes, 2007, Vol 56, pA191
- ISSN
0012-1797
- Publication type
Academic Journal