Journal
CLINICAL SCIENCE
Volume 123, Issue 5-6, Pages 375-386Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20110621
Keywords
endothelial dysfunction; Ca2+/calmodulin-dependent protein kinase (CaM kinase); NO synthase; Type 2 diabetes
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Promotion and Mutual Aid Corporation for Private Schools of Japan
Ask authors/readers for more resources
In the present sutdy, we have examined the relationship between the CaMKII (Ca2+/calmodulin-dependent protein kinase II) pathway and endothelial dysfunction in aortas from GK (Goto-Kakizaki) Type 2 diabetic rats. The ACh (acetylcholine)-induced relaxation and NO production were each attenuated in diabetic aortas (compared with those from age-matched control rats). ACh-stimulated Ser(I177)-eNOS (endothelial NO synthase) phosphorylation was significantly decreased in diabetic aortas (compared with their controls). ACh markedly increased the CaMKII phosphorylation level within endothelial cells only in control aortas (as assessed by immunohistochemistry and Western blotting). ACh-stimulated Thr(286)-CaMKII phosphorylation within endothelial cells was significantly decreased in diabetic aortas (compared with their controls). The ACh-induced relaxations, NO production, eNOS phosphorylation, and CaMKII phosphorylation were inhibited by KN93 and/or by lavendustin C (inhibitors of CaMKII) in control aortas, but not in diabetic ones. Pre-incubation of aortic strips with a PP (protein phosphatase)-I inhibitor, PPI2 (protein phosphatase inhibitor 2), or with a PP2A inhibitor, CA (cantharidic acid), corrected the above abnormalities in diabetic aortas. The expression of PP2A type A subunit was increased in diabetic aortas. The ACh-stimulated Thr(320)-phosphorylation level of PPI alpha was lower in diabetic aortas than in their controls, but the total PPI alpha protein level was not different. These results suggest that the aortic relaxation responses, NO production, and eNOS activity mediated by CaMKII phosphorylation are decreased in this Type 2 diabetic model, and that these impairments of CaMKII signalling may be, at least in part, due to enhancements of PP I a activity and PP2A expression.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available