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 O 2 − 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.