Osto Elena, Matter Christian M, Kouroedov Alexei, Malinski Tadeusz, Bachschmid Markus, Camici Giovanni G, Kilic Ulkan, Stallmach Thomas, Boren Jan, Iliceto Sabino, Lüscher Thomas F, Cosentino Francesco
Cardiology and Cardiovascular Research, Institute of Physiology, Zurich, Switzerland.
Circulation. 2008 Nov 11;118(20):2073-80. doi: 10.1161/CIRCULATIONAHA.108.765032. Epub 2008 Oct 27.
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.
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.
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.
由于活性氧的过量产生，高胆固醇血症诱导的内皮功能障碍是动脉粥样硬化形成的主要触发因素。c-Jun氨基末端激酶（JNKs）被氧化应激激活，并在动脉粥样硬化形成和炎症中起关键作用。我们研究了JNK2缺失是否能预防高胆固醇血症诱导的内皮功能障碍和氧化应激。
雄性JNK2基因敲除（JNK2(-/-)）和野生型（WT）小鼠（8周龄）分别给予高胆固醇饮食（HCD；总胆固醇1.25%）或正常饮食14周。与喂食正常饮食的WT小鼠相比，喂食HCD的WT小鼠主动脉裂解物中JNK磷酸化增加（P<0.05）。WT HCD小鼠对乙酰胆碱的内皮依赖性舒张功能受损（与WT正常饮食相比，P<0.05）。相比之下，JNK2(-/-) HCD小鼠未表现出内皮功能障碍（对乙酰胆碱的最大舒张反应为96±5%；与WT HCD相比，P<0.05）。所有组的非内皮依赖性舒张功能相同。在WT小鼠中发现高胆固醇血症诱导内皮细胞一氧化氮（NO）释放减少，但在JNK2(-/-)小鼠中未发现。同时，仅在JNK2(-/-) HCD动物中内皮型NO合酶表达上调，而在WT HCD小鼠中细胞外超氧化物歧化酶和锰超氧化物歧化酶等抗氧化防御系统的表达降低，但在JNK2(-/-) HCD小鼠中未降低。与JNK2(-/-)小鼠相比，WT HCD中O(2)(-)和ONOO(-)浓度以及硝基酪氨酸染色和过氧化增加。
JNK2作为高胆固醇血症诱导的内皮功能障碍和氧化应激的介质起关键作用。因此，JNK2可能为预防血管疾病和动脉粥样硬化提供一个新的靶点。
