Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C Potential Clinical Implications in Hypertension
Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C Potential Clinical Implications in Hypertension
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DOI：
10.1161/hypertensionaha.109.129353
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发表时间：
2009-10-01
期刊：
影响因子：
8.3
通讯作者：
Zalba, Guillermo
中科院分区：
文献类型：
--
作者：
Fortuno, Ana;Bidegain, Julen;Zalba, Guillermo
氧化应激在高血压的发病机制中起着关键作用。NADPH氧化酶构成吞噬细胞中超氧阴离子的主要来源，并且其活化与这些细胞分泌基质金属蛋白酶（MMP）-9有关。我们研究了血管紧张素II 1型受体拮抗剂氯沙坦及其代谢产物（EXP 3174和EXP 3179）对人吞噬细胞NADPH氧化酶活性和MMP-9分泌的影响。EXP 3179（而非氯沙坦和EXP 3174）剂量依赖性地抑制（P < 0.05）佛波醇肉豆蔻酸酯乙酸酯和胰岛素刺激的NADPH氧化酶活性。EXP 3179还可抑制内皮细胞中肉豆蔻酸佛波酯乙酸酯诱导的NADPH氧化酶。此外，EXP 3179抑制（P < 0.05）佛波醇肉豆蔻酸酯乙酸酯刺激的p47 phox从胞质溶胶到膜的易位和蛋白激酶C活性。亲和力实验和酶测定证实，EXP 3179抑制几种蛋白激酶C亚型。EXP 3179还抑制（P < 0.05）佛波醇肉豆蔻酸酯乙酸酯刺激的MMP-9分泌。在一项对153例高血压患者进行的研究中，与未经治疗的患者和接受其他血管紧张素II 1型受体拮抗剂或血管紧张素转换酶抑制剂治疗的患者相比，接受氯沙坦治疗的患者的吞噬细胞NADPH氧化酶活性较低（P < 0.05）。氯沙坦治疗组血浆MMP-9水平明显低于对照组（P < 0.05）。因此，EXP 3179通过靶向蛋白激酶C信号通路的潜在机制，在吞噬细胞中作为NADPH氧化酶的阻断剂。这种作用可能与这些细胞MMP-9分泌减少有关。认为EXP 3179代谢产物可能赋予氯沙坦降低高血压患者吞噬细胞介导的氧化应激的特异性能力。（高血压。2009; 54：744-750）。
Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P < 0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate-induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P < 0.05) both phorbol myristate acetate-stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P < 0.05) phorbol myristate acetate-stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P < 0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P < 0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients. (Hypertension. 2009; 54: 744-750.)