c-Jun N-Terminal kinase 2 deficiency protects against hypercholesterolemia- induced endothelial dysfunction and oxidative stress

Abstract

Background-Hypercholesterolemia-induced endothelial dysfunction due to excessive production of reactive oxygen species is a major trigger of atherogenesis. The c-Jun-N-terminal kinases (JNKs) are activated by oxidative stress and play a key role in atherogenesis and inflammation. We investigated whether JNK2 deletion protects from hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Methods and Results-Male JNK2 knockout (JNK2-/-) and wild-type (WT) mice (8 weeks old) were fed either a high-cholesterol diet (HCD; 1.25% total cholesterol) or a normal diet for 14 weeks. Aortic lysates of WT mice fed a HCD showed an increase in JNK phosphorylation compared with WT mice fed a normal diet (P<0.05). Endothelium-dependent relaxations to acetylcholine were impaired in WT HCD mice (P<0.05 versus WT normal diet). In contrast, JNK2-/- HCD mice did not exhibit endothelial dysfunction (96±5% maximal relaxation in response to acetylcholine; P<0.05 versus WT HCD). Endothelium-independent relaxations were identical in all groups. A hypercholesterolemia-induced decrease in nitric oxide (NO) release of endothelial cells was found in WT but not in JNK2 -/- mice. In parallel, endothelial NO synthase expression was upregulated only in JNK2-/- HCD animals, whereas the expression of antioxidant defense systems such as extracellular Superoxide dismutase and manganese Superoxide dismutase was decreased in WT but not in JNK2-/- HCD mice. In contrast to JNK2-/- mice, WT HCD displayed an increase in O2- and ONOO" concentrations as well as nitrotyrosine staining and peroxidation. Conclusions-JNK2 plays a critical role as a mediator of hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Thus, JNK2 may provide a novel target for prevention of vascular disease and atherosclerosis. © 2008 American Heart Association, Inc.