JNK 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress

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. DOI: https://doi.org/10.1161/CIRCULATIONAHA.108.765032 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-11304 Accepted Version Originally published at: Osto, E; Matter, C M; Kouroedov, A; Malinski, T; Bachschmid, M; Camici, G G; Kilic, U; Stallmach, T; Boren, J; Iliceto, S; Lüscher, T F; Cosentino, F (2008). c-Jun N-terminal kinase 2 deficiency protects against hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Circulation, 118(20):2073-2080. DOI: https://doi.org/10.1161/CIRCULATIONAHA.108.765032 JNK2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress Elena Osto MD, Christian M. Matter MD, 1,2 Alexey Kouroedov MD, PhD, Tadeusz Malinski PhD, Markus Bachschmid PhD, 1,2 Giovanni Camici PhD, 1,2 Ulkan Kilic PhD, Thomas Stallmach MD, Jan Boren PhD, 7 Sabino Iliceto MD, Thomas F. Luscher MD, Francesco Cosentino MD, PhD Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland; Department of Biochemistry, Ohio University, Athens, Ohio; Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Department of Pathology, University Hospital, Zurich, Switzerland; Wallenberg Laboratory Sahlgrenska Academy, Goteborg, Sweden, 7 Cardiology, University of Padua, Cardiology, 2 Faculty of Medicine, University “Sapienza”, Rome, Italy, Running title: Role of JNK2 in endothelial dysfunction Address for Correspondence: Francesco Cosentino, M.D., Ph.D. Cardiology & Cardiovascular Research Institute of Physiology University of Zurich-Irchel Winterthurerstrasse, 190 CH-8057 Zurich, Switzerland Tel: 41-44-635 5097 Fax: 41-44-635 6827 Email: f_cosentino@hotmail.com