Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL, 60612, USA
Adv Exp Med Biol. 2010;661:155-67. doi: 10.1007/978-1-60761-500-2_10.
Oxidative [Au1]stress, through the production of oxygen metabolites such as hydrogen peroxide[Au2] (H(2)O(2)), increases vascular endothelial permeability and plays a crucial role in several lung diseases. The transient receptor potential (melastatin) 2 (TRPM2) is an oxidant-sensitive, nonselective cation channel that is widely expressed in mammalian tissues, including the vascular endothelium. We have demonstrated the involvement of TRPM2 in mediating oxidant-induced calcium entry and endothelial hyperpermeability in cultured pulmonary artery endothelial cells. Here, we provide evidence that neutrophil activation-dependent increase in endothelial permeability and neutrophil extravasation requires TRPM2 in cultured endothelial cells. In addition, protein kinase Calpha (PKCalpha) that rapidly colocalizes with the short (nonconducting) TRPM2 isoform after exposure to hydrogen peroxide positively regulates calcium entry through the functional TRPM2 channel. Thus, increase in lung microvessel permeability and neutrophil sequestration depends on the activation of endothelial TRPM2 by neutrophilic oxidants and on PKCalpha regulation of TRPM2 channel activity. Manipulating TRPM2 function in the endothelium may represent a novel strategy aimed to prevent oxidative stress-related vascular dysfunction.
氧化应激通过产生氧代谢物，如过氧化氢[Au2]（H(2)O(2)），增加血管内皮通透性，并在几种肺部疾病中发挥关键作用。瞬时受体电位（melastatin）2（TRPM2）是一种氧化剂敏感的非选择性阳离子通道，广泛表达于哺乳动物组织中，包括血管内皮。我们已经证明了 TRPM2 在介导培养的肺动脉内皮细胞中氧化剂诱导的钙内流和内皮通透性增加中的作用。在这里，我们提供的证据表明，中性粒细胞激活依赖性的内皮通透性增加和中性粒细胞外渗需要在培养的内皮细胞中TRPM2。此外，蛋白激酶 Calpha（PKCalpha）在暴露于过氧化氢后迅速与短（非传导）TRPM2 异构体共定位，正向调节通过功能性 TRPM2 通道的钙内流。因此，肺微血管通透性增加和中性粒细胞扣押取决于内皮 TRPM2 被中性粒细胞氧化剂激活，以及 PKCalpha 对 TRPM2 通道活性的调节。在内皮细胞中操纵 TRPM2 功能可能代表一种新的策略，旨在预防与氧化应激相关的血管功能障碍。
