Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction.
Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction.
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DOI：
10.1161/circulationaha.108.784298
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发表时间：
2008-09-23
期刊：
影响因子：
37.8
通讯作者：
Keaney JF Jr
中科院分区：
文献类型：
--
作者：
Schulz E;Dopheide J;Schuhmacher S;Thomas SR;Chen K;Daiber A;Wenzel P;Münzel T;Keaney JF Jr
Oxidative injury and dysfunction of the vascular endothelium is an early and causal feature of many vascular diseases and single antioxidant strategies to prevent vascular injury have met with mixed results. Here we report that induction of a metabolic stress response with AMP kinase prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1α (PGC-1α) is a key downstream target of AMPK that is both necessary and sufficient for the metabolic stress response and JNK attenuation. Moreover, induction of the metabolic stress response in vivo attenuates ROS-mediated JNK activation and endothelial dysfunction in response to angiotensin II in wild-type mice, but not animals lacking either the endothelial isoform of AMPK or PGC-1α. These data highlight AMPK and PGC-1α as potential therapeutic targets for the amelioration of endothelial dysfunction and, as a consequence, vascular disease.
