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(Circulation. 2008;118:2073-2080.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress

Elena Osto, MD; Christian M. Matter, MD; Alexei Kouroedov, MD, PhD; Tadeusz Malinski, PhD; Markus Bachschmid, PhD; Giovanni G. Camici, PhD; Ulkan Kilic, PhD; Thomas Stallmach, MD; Jan Boren, PhD; Sabino Iliceto, MD; Thomas F. Lüscher, MD; Francesco Cosentino, MD, PhD

From Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zurich, Switzerland (E.O., C.M.M., A.K., G.G.C., U.K., T.F.L., F.C.); Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (E.O., C.M.M., A.K., G.G.C., U.K., T.F.L., F.C.); Department of Biochemistry, Ohio University, Athens, Ohio (T.M.); Department of Medicine, Boston University School of Medicine, Boston, Mass (M.B.); Department of Pathology, University Hospital, Zurich, Switzerland (T.S.); Wallenberg Laboratory, Sahlgrenska Academy, Goteborg, Sweden (J.B.); Department of Cardiology, University of Padua, Padua, Italy (S.I.); and Department of Cardiology, Second Faculty of Medicine, University Sapienza, Rome, Italy (F.C.).

Correspondence to Francesco Cosentino, MD, PhD, Cardiology and Cardiovascular Research, Institute of Physiology, University of Zurich-Irchel, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail f_cosentino{at}hotmail.com

Received January 11, 2008; accepted August 26, 2008.

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.

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Clinical Summaries
Circulation 2008 118: 2013-2014. [Extract] [Full Text]