Abstract 915: Deletion of JNK2 Prevents Hypercholesterolemia-Induced Oxidative Stress and Endothelial Dysfunction
Background Hypercholesterolemia-induced endothelial dysfunction (ED) is a major trigger for atherosclerosis. The c-Jun-N-terminal kinases (JNKs) belong to the mitogen-activated protein kinase family. Genetic deletion of JNK2 has been shown to decrease atheroma formation. The present study was designed to investigate whether hypercholesterolemic JNK2 knockout (JNK2−/−) mice are protected from oxidative stress-induced ED.
Methods and Results Male JNK2−/− and corresponding wild-type (WT) mice (8 weeks old) were fed either a high cholesterol diet (HCD, 1.25% total cholesterol) or normal chow (controls) for 14 weeks. WT mice fed a HCD showed a 2-fold increase in JNK phosphorylation as assessed by Western blotting (n=4 – 6, p<0.05 vs. controls). In parallel, endothelium-dependent relaxations to acetylcholine (Ach, 10−9-10−6 mol/L) were impaired in WT mice exposed to a HCD as compared to WT controls (n=4 – 6 in each groups, p<0.05). In contrast, JNK2−/− mice did not exhibit hypercholesterolemia-induced ED (96±5% max relaxation to Ach, n=4 – 6, p<0.05 vs. WT HCD). Endothelium-independent relaxations to sodium nitroprusside (10−10-10−5 mol/L) were identical in all groups. Nitric oxide release, measured by nanosensors in single aortic endothelial cells, was decreased in WT but not in JNK2−/− HCD mice (121 vs. 253 nmol/L in WT and JNK2−/− HCD mice, respectively, n=4 – 6, p<0.05). Indeed, WT HCD mice displayed a marked increase in peroxynitrite (ONOO−) generation, nitrotyrosine expression,and lipid peroxidation (n=4 – 6 in each groups, p<0.05 vs. WT and JNK2−/− control as well as JNK2−/− HCD mice). Deletion of the JNK2 gene prevented this hypercholesterolemia-induced increase in oxidative stress. Furthermore, expression of antioxidant defense systems such as manganese and extracellular superoxide dismutase as well as heme-oxygenase activity was significantly decreased in WT, but not in JNK2−/− HCD mice (n=4 – 6, p<0.05).
Conclusions These data suggest that genetic deletion of JNK2 protects against hypercholesterolemia-induced oxidative stress and endothelial dysfunction. Thus, inhibition of JNK2 may represent a novel therapeutic target to prevent initiation of atherogenesis.