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Leptin and the regulation of endothelial function in physiological and pathological conditions

机译：生理和病理条件下瘦素与内皮功能的调节

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摘要

Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser 1177, increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone.
机译：肥胖及其伴随的代谢综合征是与内皮功能障碍有关的心血管疾病的最重要原因，例如动脉高血压和动脉粥样硬化。肥胖的这种有害作用部分地由脂肪组织激素瘦素的过量产生介导。在生理条件下，瘦素通过刺激一氧化氮（NO）和内皮衍生的超极化因子（EDHF）诱导内皮依赖性血管舒张。瘦蛋白通过涉及AMP激活的蛋白激酶（AMPK）和蛋白激酶B / Akt的机制激活内皮一氧化氮合酶（eNOS），后者会在Ser 1177处磷酸化eNOS，从而增加其活性。在诸如肥胖症和代谢综合征的病理条件下，瘦素的NO介导的血管舒张作用受损。对瘦素的急性NO模仿作用的抵抗力是由慢性高脂血症引起的，并且可能由不同的机制引起，例如瘦素受体的下调，循环C反应蛋白水平的升高，氧化应激和细胞因子信号传导抑制剂3的过表达。在持续性肥胖症中，瘦素诱导的NO生成受损可通过EDHF进行补偿。但是，在晚期代谢综合征中，EDHF对瘦素的血液动力学作用的贡献变得无效。对瘦素的血管舒张作用的抗性可能由于这种激素对交感神经系统的无相反刺激而导致了动脉高压的发展。

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