Abstract 11517: Inhibition of CaMKII- and ERK-Mediated eNOS Phosphorylation Impairs Endothelial Function in Renal Failure Mice: New Effect of Asymmetric Dimethylarginine
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 additional effects other than the competitive inhibition of L-arginine. We sought to examine whether increased ADMA causes endothelial dysfunction in a CKD model and if so, to investigate the molecular mechanism.
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 (Ser1177) 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, the agonist-induced phosphorylations of eNOS (Ser1177) and the upstream kinases, such as calcium/calmodulin-dependent protein kinase II (CaMKII) (Thr286) and extracellular signal-related kinase (ERK) 1/2 (Thr202/Tyr204) phosphorylation, but not Akt (Ser473), were decreased by ADMA at the concentrations smaller than that of L-arginine in the culture media.
Conclusions- Elevated circulating ADMA is the cause, but not an epiphenomenon, of endothelial dysfunction in CKD. This effect may be attributable to inhibition of the CaMKII- and ERK-mediated eNOS phosphorylation, a novel mechanism by which ADMA impairs eNOS function.
- © 2011 by American Heart Association, Inc.