Carpéné Christian, Bizou Mathilde, Tréguer Karine, Hasnaoui Mounia, Grès Sandra
Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale (INSERM U1048), Toulouse, France,
J Physiol Biochem. 2015 Sep;71(3):487-96. doi: 10.1007/s13105-014-0379-3. Epub 2015 Jan 9.
Glitazones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists widely used as antidiabetic drugs also known as thiazolidinediones. Most of them exert other effects such as anti-inflammatory actions via mechanisms supposed to be independent from PPARγ activation (e.g., decreased plasma monocyte chemoattractant protein-1 (MCP-1) levels). Recently, pioglitazone has been shown to inhibit the B form of monoamine oxidase (MAO) in mouse, while rosiglitazone and troglitazone were described as non-covalent inhibitors of both human MAO A and MAO B. Since molecules interacting with MAO might also inhibit semicarbazide-sensitive amine oxidase (SSAO), known as vascular adhesion protein-1 (VAP-1), and since VAP-1/SSAO inhibitors exhibit anti-inflammatory activity, our aim was to elucidate whether VAP-1/SSAO inhibition could be a mechanism involved in the anti-inflammatory behaviour of glitazones. To this aim, MAO and SSAO activities were measured in human subcutaneous adipose tissue biopsies obtained from overweight women undergoing plastic surgery. The production of hydrogen peroxide, an end-product of amine oxidase activity, was determined in tissue homogenates using a fluorometric method. The oxidation of 1 mM tyramine was inhibited by pargyline and almost resistant to semicarbazide, therefore predominantly MAO-dependent. Rosiglitazone was more potent than pioglitazone in inhibiting tyramine oxidation. By contrast, benzylamine oxidation was only abolished by semicarbazide: hence SSAO-mediated. Pioglitazone hampered SSAO activity only when tested at 1 mM while rosiglitazone was inefficient. However, rosiglitazone exhibited anti-inflammatory activity in human adipocytes by limiting MCP-1 expression. Our observations rule out any involvement of VAP-1/SSAO inhibition and subsequent limitation of leukocyte extravasation in the anti-inflammatory action of glitazones.
格列酮类药物是过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，作为抗糖尿病药物被广泛使用，也被称为噻唑烷二酮类。它们中的大多数还发挥其他作用，例如通过被认为独立于PPARγ激活的机制产生抗炎作用（例如，降低血浆单核细胞趋化蛋白-1（MCP-1）水平）。最近，已证明吡格列酮可抑制小鼠单胺氧化酶（MAO）的B型，而罗格列酮和曲格列酮被描述为人类MAO A和MAO B的非共价抑制剂。由于与MAO相互作用的分子也可能抑制氨基脲敏感胺氧化酶（SSAO），即血管粘附蛋白-1（VAP-1），并且由于VAP-1/SSAO抑制剂具有抗炎活性，我们的目的是阐明VAP-1/SSAO抑制是否可能是格列酮类药物抗炎行为所涉及的机制。为此，在从接受整形手术的超重女性获得的人皮下脂肪组织活检中测量了MAO和SSAO活性。使用荧光法在组织匀浆中测定胺氧化酶活性的终产物过氧化氢的产生。1 mM酪胺的氧化被帕吉林抑制，并且几乎对氨基脲有抗性，因此主要是MAO依赖性的。罗格列酮在抑制酪胺氧化方面比吡格列酮更有效。相比之下，苄胺氧化仅被氨基脲消除：因此是SSAO介导的。吡格列酮仅在1 mM测试时才阻碍SSAO活性，而罗格列酮无效。然而，罗格列酮通过限制MCP-1表达在人脂肪细胞中表现出抗炎活性。我们的观察结果排除了VAP-1/SSAO抑制以及随后白细胞外渗受限参与格列酮类药物抗炎作用的任何可能性。
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