Abstract
Inhibition of CaMKII/ERK-Mediated eNOS Phosphorylation Impairs Endothelial Function in Renal Failure Mice: New Effect of AsymmetricDimethylarginine
Journal of cardiac failure, Vol.18(10 Suppl), pp.S151-S152
10/01/2012
DOI: 10.1016/j.cardfail.2012.08.141
Abstract
Background
Patients with chronic kidney disease (CKD) showed the elevation of circulating asymmetric dimethylarginine (ADMA). Recent studies suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) via effects other than competition with the substrate L-arginine. We sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a CKD model.
Methods and Results
In wild-type mice, 5/6 nephrectomy increased blood urea nitrogen and serum creatinine by 2.5- and 2-fold, respectively, and elevated circulating ADMA by 20% without blood pressure change. Nephrectomy deteriorated endothelium-dependent relaxation and reduced eNOS phosphorylation of isolated aortic rings. In transgenic (TG) mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was decreased to half that of wild-type mice and was not increased by nephrectomy. The nephrectomy-induced deterioration of endothelium-dependent relaxation and eNOS phosphorylation was abolished in TG mice. In cultured human endothelial cells, agonist-induced phosphorylations of eNOS and the upstream kinases, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-related kinase (ERK) 1/2 phosphorylation, but not Akt, were decreased by ADMA at concentrations less than that of L-arginine in the media.
Conclusions
Elevated circulating ADMA is the cause, not an epiphenomenon, of endothelial dysfunction in CKD. Inhibition of the CaMKII- and ERK-mediated eNOS phosphorylation may be a novel mechanism by which ADMA impairs eNOS function.
Details
- Title: Subtitle
- Inhibition of CaMKII/ERK-Mediated eNOS Phosphorylation Impairs Endothelial Function in Renal Failure Mice: New Effect of AsymmetricDimethylarginine
- Creators
- Hidemi Kajimoto - Kurume UniversityHisashi Kai - Kurume UniversityHiroki Aoki - Kurume UniversityHiroki Uchiwa - Kurume UniversityYuji Aoki - Kurume UniversityTsutomu Imaizumi - Kurume University
- Resource Type
- Abstract
- Publication Details
- Journal of cardiac failure, Vol.18(10 Suppl), pp.S151-S152
- DOI
- 10.1016/j.cardfail.2012.08.141
- ISSN
- 1071-9164
- eISSN
- 1532-8414
- Publisher
- Elsevier Inc
- Language
- English; Japanese
- Date published
- 10/01/2012
- Academic Unit
- Cardiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984961024302771
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