Tsai Ming-Horng, Lee Chiang-Wen, Hsu Lee-Fen, Li Shu-Yu, Chiang Yao-Chang, Lee Ming-Hsueh, Chen Chun-Han, Liang Hwey-Fang, How Jia-Mei, Chang Pey-Jium, Wu Ching-Mei, Lee I-Ta
Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan.
Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
Redox Biol. 2017 Aug;12:377-388. doi: 10.1016/j.redox.2017.02.019. Epub 2017 Mar 1.
Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47 translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.
血管紧张素II（Ang II）参与了心血管疾病的发病机制，基质金属蛋白酶-9（MMP-9）诱导的人主动脉平滑肌细胞（HASMCs）迁移是最常见和基本的病理特征。一氧化碳（CO）是血红素加氧酶分解血红素的副产物，在各种组织和器官系统中发挥抗炎作用。在本研究中，我们旨在探讨一氧化碳释放分子-2（CORM-2）对Ang II诱导的HASMCs中MMP-9表达和细胞迁移的影响及潜在机制。Ang II显著上调HASMCs中MMP-9的表达和细胞迁移，用p47、Nox2、Nox4、p65、血管紧张素II 1型受体（AT1R）的小干扰RNA（siRNA）转染以及用NADPH氧化酶、活性氧（ROS）和核因子κB（NF-κB）抑制剂预处理可抑制这种上调。此外，Ang II还诱导NADPH氧化酶/ROS生成以及p47从胞质溶胶转位到细胞膜。而且，用CORM-2预处理可抑制Ang II诱导的氧化应激和MMP-9依赖性细胞迁移。最后，我们观察到Ang II通过AT1R而非AT2R诱导HASMCs释放白细胞介素-6（IL-6），这可进一步导致MMP-9分泌和细胞迁移。用CORM-2预处理可减少Ang II诱导的IL-6释放。总之，CORM-2通过抑制NADPH氧化酶/ROS生成、使NF-κB失活以及抑制IL-6/MMP-9表达来抑制Ang II诱导的HASMCs迁移。因此，应用CO，尤其是CORM-2，是逆转各种心血管疾病病理变化的一种潜在对策。还需要进一步开展旨在鉴定以CO为靶点的新型心脏和血管保护性抗氧化和抗炎物质的研究，并建立精心设计的体内模型以恰当评估这些药物的疗效。
