Leptin Potentiates Endothelium-Dependent Relaxation by Inducing Endothelial Expression of Neuronal NO Synthase
Leptin Potentiates Endothelium-Dependent Relaxation by Inducing Endothelial Expression of Neuronal NO Synthase
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DOI：
10.1161/atvbaha.112.251140
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发表时间：
2012-07-01
影响因子：
8.7
通讯作者：
Schroeder, Katrin
中科院分区：
文献类型：
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作者：
Benkhoff, Sebastian;Loot, Annemarieke E.;Schroeder, Katrin
肥胖与高瘦素血症有关，但尚不清楚瘦素是否保护血管功能或促进功能障碍。因此，我们研究的后果，高瘦素血症瘦mice.Methods和结果野生型和内皮型一氧化氮合酶（eNOS）（-/-）小鼠输注瘦素（0.4毫克/公斤，每天，7天），和内皮依赖性舒张主动脉段进行了研究。在正常野生型小鼠中，瘦素对乙酰胆碱诱导的内皮依赖性舒张没有影响，但在用血管紧张素II（0.7 mg/kg/天，7天）诱导内皮功能障碍的野生型小鼠中，瘦素恢复了内皮依赖性舒张。瘦素还使eNOS（-/-）小鼠的睾丸对乙酰胆碱敏感，这种作用被神经元NOS（nNOS）抑制所阻断，并且在eNOS-nNOS双（-/-）小鼠中未观察到。与这些研究结果一致，瘦素诱导nNOS表达在小鼠和人类血管和人类内皮细胞，但不是平滑肌细胞。高脂饮食也诱导小鼠主动脉nNOS表达。机械地，瘦素增加内皮Janus激酶2和信号转导和转录激活因子3磷酸化，抑制Janus激酶2阻止nNOS诱导培养细胞和瘦素诱导的松弛eNOS（-/-）mice. Conclusion瘦素诱导内皮nNOS表达，这部分补偿了eNOS缺乏NO产生，以维持内皮依赖性松弛。（Arterioscler Thromb Vasc Biol.2012;32：1605-1612.）
Objective-Obesity is associated with hyperleptinemia but it is not clear whether leptin protects vascular function or promotes dysfunction. We therefore studied the consequences of hyperleptinemia in lean mice.Methods and Results-Wild-type and endothelial NO synthase (eNOS)(-/-) mice were infused with leptin (0.4 mg/kg per day, 7 days), and endothelium-dependent relaxation was studied in aortic segments. Leptin had no effect on acetylcholine-induced endothelium-dependent relaxation in normal wild-type mice but restored endothelium-dependent relaxation in wild-type mice treated with angiotensin II (0.7 mg/kg per day, 7 days) to induce endothelial dysfunction. Leptin also sensitized aortae from eNOS(-/-) mice to acetylcholine, an effect blocked by neuronal NOS (nNOS) inhibition and not observed in eNOS-nNOS double(-/-) mice. Consistent with these findings, leptin induced nNOS expression in murine and human vessels and human endothelial but not smooth muscle cells. Aortic nNOS expression was also induced in mice by a high-fat diet. Mechanistically, leptin increased endothelial Janus kinase 2 and signal transducer and activator of transcription 3 phosphorylation, and inhibition of Janus kinase 2 prevented nNOS induction in cultured cells and leptin-induced relaxations in eNOS(-/-) mice.Conclusion-Leptin induces endothelial nNOS expression, which compensates, in part, for a lack of NO production by eNOS to maintain endothelium-dependent relaxation. (Arterioscler Thromb Vasc Biol. 2012;32:1605-1612.)