Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, Oklahoma City, OK 73126-0901, USA.
Hypertension. 2012 Sep;60(3):818-26. doi: 10.1161/HYPERTENSIONAHA.112.199281. Epub 2012 Jul 9.
The normal IgG, a circulating antibody, is maintained at a constant level in humans. However, little is known regarding whether normal IgG has effects on the function of vascular endothelial cells. The purpose of this study was to investigate whether IgG affects superoxide (O(2)(·-)) generation and cell permeability in human aortic endothelial cells (HAECs) isolated from a hypertensive patient. The effect of normal human IgG on endothelial cell function was investigated in cultured HAECs isolated from a hypertensive patient who died of stroke. The results demonstrated, for the first time, that normal IgG attenuated the intracellular O(2)(·-) level and decreased cell migration, cell permeability, and stress fiber formation in HAECs. IgG significantly decreased Rac1 activity and NADPH oxidase activity but upregulated Mn superoxide dismutase expression in HAECs, which may contribute to the IgG-induced decrease in O(2)(·-) level. It is noted that AMP-activated protein kinase (AMPK) was activated by IgG, as evidenced by increased phosphorylation of AMPK. Interestingly, inhibition of AMPK by an AMPK inhibitor abolished IgG-induced decreases in Rac1 and NADPH oxidase activities and IgG-induced increases in Mn superoxide dismutase expression, suggesting that AMPK is an important mediator of the IgG-induced regulation of these enzymes. Importantly, inhibition of AMPK activity also prevented the IgG-induced decrease in O(2)(·-) levels, cell migration, cell permeability, and stress fiber formation. Therefore, normal human IgG may protect HAECs via activation of AMPK and subsequent decreases in intracellular O(2)(·-). These findings reveal a previously unidentified role of normal IgG in regulating AMPK and endothelial cell function.
正常 IgG 是一种循环抗体，在人体内保持恒定水平。然而，目前对于正常 IgG 是否对血管内皮细胞的功能有影响知之甚少。本研究旨在探讨 IgG 是否会影响高血压患者分离的人主动脉内皮细胞（HAEC）中超氧化物（O(2)(·-))的生成和细胞通透性。从死于中风的高血压患者中分离出 HAEC，研究正常 IgG 对内皮细胞功能的影响。结果首次表明，正常 IgG 可减弱 HAEC 中的细胞内 O(2)(·-)水平，并降低细胞迁移、细胞通透性和应力纤维形成。IgG 可显著降低 Rac1 活性和 NADPH 氧化酶活性，但可上调 HAEC 中 Mn 超氧化物歧化酶的表达，这可能是 IgG 诱导 O(2)(·-)水平降低的原因。值得注意的是，IgG 激活了 AMP 激活的蛋白激酶（AMPK），这一点可通过 AMPK 的磷酸化增加来证明。有趣的是，AMPK 抑制剂可抑制 IgG 诱导的 Rac1 和 NADPH 氧化酶活性降低以及 IgG 诱导的 Mn 超氧化物歧化酶表达增加，表明 AMPK 是 IgG 诱导这些酶调节的重要介质。重要的是，抑制 AMPK 活性也可防止 IgG 诱导的 O(2)(·-)水平、细胞迁移、细胞通透性和应力纤维形成降低。因此，正常 IgG 可能通过激活 AMPK 并随后降低细胞内 O(2)(·-)来保护 HAEC。这些发现揭示了正常 IgG 在调节 AMPK 和内皮细胞功能方面的一个以前未被识别的作用。
