Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
复制标题
血浆卡利他汀减少与冠状动脉疾病的严重程度相关，卡利他汀治疗可减轻小鼠动脉粥样硬化斑块的形成。
DOI：
10.1161/jaha.118.009562
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发表时间：
2018-11-06
影响因子：
5.4
通讯作者：
Chao, Julie
中科院分区：
文献类型：
--
作者：
Yao, Yuyu;Li, Bing;Chao, Julie
背景——卡利他汀通过抑制氧化应激和炎症对器官损伤发挥有益作用。然而，卡利他汀在动脉粥样硬化中的作用尚不清楚。在这里，我们研究了卡利他汀在冠状动脉疾病（CAD）患者、apoE（-/-）小鼠动脉粥样硬化斑块以及内皮激活中的作用和机制。方法和结果--分析了 453 名 CAD 不同阶段患者的血浆卡利他汀水平。 CAD 患者的卡利司他水平显着较低，并且与 CAD 严重程度和氧化应激呈负相关。部分颈动脉结扎后，将腺病毒载体中的人卡利他汀 cDNA 静脉注射到 apoE(-/-) 小鼠体内，使用或不使用一氧化氮合酶抑制剂（Nx-硝基-L-精氨酸甲酯）或 Sirtuin 1 抑制剂（烟酰胺）。与对照腺病毒注射相比，卡利他汀基因递送显着减少颈动脉中的巨噬细胞沉积、氧化应激和斑块体积。 Kallistatin 给药可增加颈动脉斑块中内皮一氧化二氮合酶、去乙酰化酶 1、白细胞介素 10、超氧化物歧化酶 2 和过氧化氢酶的表达。 Nx-硝基-L-精氨酸甲酯或烟酰胺减轻了卡利他汀对小鼠的有益作用。此外，人卡利司他蛋白可抑制肿瘤坏死因子 a 诱导的 NADPH 氧化酶活性，并增加培养的人内皮细胞中内皮一氧化二氮合酶和 Sirtuin 1 的表达。 Nx-硝基-L-精氨酸甲酯或烟酰胺也消除了这些作用。 结论——这是第一项证明患者血浆卡利他汀水平降低与 CAD 严重程度和氧化应激相关的研究。 Kallistatin 治疗通过刺激 Sirtuin 1/内皮一氧化二氮合酶途径来预防小鼠颈动脉粥样硬化斑块的形成。这些发现表明卡利他汀对人类受试者和小鼠模型的动脉粥样硬化具有潜在的保护作用。
Background--Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (CAD), atherosclerotic plaques of apoE(-/-) mice, and endothelial activation.Methods and Results--Plasma kallistatin levels were analyzed in 453 patients at different stages of CAD. Kallistatin levels were significantly lower in patients with CAD and negatively associated with CAD severity and oxidative stress. Human kallistatin cDNA in an adenoviral vector was injected intravenously into apoE(-/-) mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (Nx-nitro-L-arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin-10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by Nx-nitro-L-arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor-a-induced NADPH oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by Nx-nitro-L-arginine methyl ester or nicotinamide.Conclusions--This was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with CAD severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models.