Division of Cardiovascular Sciences, Centre for Applied Medical Research, Pamplona, Spain.
J Hypertens. 2010 Sep;28(9):1944-50. doi: 10.1097/HJH.0b013e32833c21af.
Hyperleptinemia and oxidative stress play a major role in the development of cardiovascular diseases in obesity. This study aimed to investigate whether there is a relationship between plasma levels of leptin and phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and its potential relevance in the vascular remodeling in obese patients.
The study was performed in 164 obese and 94 normal-weight individuals (controls). NADPH oxidase activity was evaluated by luminescence in phagocytic cells. Levels of leptin were quantified by ELISA in plasma samples. Carotid intima-media thickness (cIMT) was measured by ultrasonography. In addition, we performed in-vitro experiments in human peripheral blood mononuclear cells and murine macrophages.
Phagocytic NADPH oxidase activity and leptin levels were enhanced (P < 0.05) in obese patients compared with controls. NADPH oxidase activity positively correlated with leptin in obese patients. This association remained significant in a multivariate analysis. cIMT was higher (P < 0.05) in obese patients compared with controls. In addition, cIMT also correlated positively with leptin and NADPH oxidase activity in obese patients. In-vitro studies showed that leptin induced NADPH oxidase activation. Inhibition of the leptin-induced NADPH oxidase activity by wortmannin and bisindolyl maleimide suggested a direct involvement of the phosphatidylinositol 3-kinase and protein kinase C pathways, respectively. Finally, leptin-induced NADPH oxidase activation promoted macrophage proliferation.
These findings show that phagocytic NADPH oxidase activity is increased in obesity and is related to preclinical atherosclerosis in this condition. We also suggest that hyperleptinemia may contribute to phagocytic NADPH oxidase overactivity in obesity.
瘦素血症和氧化应激在肥胖患者心血管疾病的发生发展中起着重要作用。本研究旨在探讨血浆瘦素水平与吞噬细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性之间是否存在相关性，及其在肥胖患者血管重构中的潜在相关性。
该研究纳入了 164 名肥胖患者和 94 名正常体重者（对照组）。通过吞噬细胞发光法评估 NADPH 氧化酶活性。采用 ELISA 法检测血浆样本中的瘦素水平。通过超声测量颈动脉内膜中层厚度（cIMT）。此外，我们还在人外周血单核细胞和鼠巨噬细胞中进行了体外实验。
与对照组相比，肥胖患者的吞噬细胞 NADPH 氧化酶活性和瘦素水平升高（P<0.05）。NADPH 氧化酶活性与肥胖患者的瘦素呈正相关。多变量分析显示这种相关性仍然显著。与对照组相比，肥胖患者的 cIMT 更高（P<0.05）。此外，肥胖患者的 cIMT 也与瘦素和 NADPH 氧化酶活性呈正相关。体外研究表明，瘦素诱导 NADPH 氧化酶激活。wortmannin 和双吲哚基马来酰亚胺分别抑制瘦素诱导的 NADPH 氧化酶活性，提示其分别涉及磷脂酰肌醇 3-激酶和蛋白激酶 C 途径。最后，瘦素诱导的 NADPH 氧化酶激活促进了巨噬细胞增殖。
这些发现表明，吞噬细胞 NADPH 氧化酶活性在肥胖中增加，并与该状态下的临床前动脉粥样硬化有关。我们还表明，瘦素血症可能导致肥胖患者吞噬细胞 NADPH 氧化酶过度活跃。
