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 Ser1177-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 Thr286-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)-1 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 Thr320-phosphorylation level of PP1α was lower in diabetic aortas than in their controls, but the total PP1α 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 PP1α activity and PP2A expression.
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Research Article|
May 29 2012
Involvement of CaM kinase II in the impairment of endothelial function and eNOS activity in aortas of Type 2 diabetic rats1
Tsuneo Kobayashi;
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
Correspondence: Professor Tsuneo Kobayashi (email [email protected]).
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Shingo Nemoto;
Shingo Nemoto
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Keiko Ishida;
Keiko Ishida
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Kumiko Taguchi;
Kumiko Taguchi
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Takayuki Matsumoto;
Takayuki Matsumoto
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Katsuo Kamata
Katsuo Kamata
1Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Publisher: Portland Press Ltd
Received:
December 01 2011
Revision Received:
March 22 2012
Accepted:
April 12 2012
Accepted Manuscript online:
April 12 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 123 (6): 375–386.
Article history
Received:
December 01 2011
Revision Received:
March 22 2012
Accepted:
April 12 2012
Accepted Manuscript online:
April 12 2012
Citation
Tsuneo Kobayashi, Shingo Nemoto, Keiko Ishida, Kumiko Taguchi, Takayuki Matsumoto, Katsuo Kamata; Involvement of CaM kinase II in the impairment of endothelial function and eNOS activity in aortas of Type 2 diabetic rats. Clin Sci (Lond) 1 September 2012; 123 (6): 375–386. doi: https://doi.org/10.1042/CS20110621
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