Involvement of CaM kinase II in impairments of endothelial function and eNOS activity in aortas of type 2 diabetic Goto‐Kakizaki rats

Abstract

We examined the relationship between calcium/calmodulin‐dependent protein kinase II (CaMKII) pathway and endothelial dysfunction in aortas from Goto‐Kakizaki type 2 diabetic rats. The ACh‐induced relaxation, NO production and Ser1177‐endothelial NO synthase (eNOS) phosphorylation were attenuated in diabetic aortas (vs. controls). ACh increased the CaMKII phosphorylation within endothelial cells only in control aortas. ACh‐stimulated Thr286‐CaMKII phosphorylation within endothelial cells was decreased in diabetic aortas (vs. controls). ACh‐induced relaxation, NO production, and phosphorylation of eNOS and CaMKII were inhibited by CaMKII inhibitors in control aortas, but not in diabetic ones. Preincubation of aortic strips with a protein phosphatase‐1 inhibitor or with a protein phosphatase‐2A (PP2A) inhibitor 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 type 2 diabetic model, and that these impairments of CaMKII signaling may be due to enhancements of PP1α activity and PP2A expression.