Inhibitory effects of vasostatin-1 against atherogenesis
Inhibitory effects of vasostatin-1 against atherogenesis
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DOI：
10.1042/cs20180451
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发表时间：
2018-12-12
期刊：
影响因子：
6
通讯作者：
Watanabe, Takuya
中科院分区：
文献类型：
--
作者：
Sato, Yuki;Watanabe, Rena;Watanabe, Takuya
Vasostatin-1是一种由嗜铬粒蛋白A（CgA）衍生的肽（76个氨基酸），已知其抑制血管收缩和血管生成。最近的研究表明，vasostatin-1通过下调粘附分子抑制人U937单核细胞与人内皮细胞（HEC）的粘附。本研究评价了血管抑素-1在人动脉粥样硬化病变中的表达及其对HEC和人THP-1单核细胞衍生的巨噬细胞的炎症反应、巨噬细胞泡沫细胞形成、人主动脉平滑肌细胞（HASMCs）的迁移和增殖以及HASMCs的细胞外基质（ECM）产生的影响，以及载脂蛋白E缺陷（ApoE（-/-））小鼠动脉粥样硬化形成的影响。Vasostatin-1在人桡动脉Monckeberg's内侧钙化硬化周围表达。Vasostatin-1抑制脂多糖（LPS）诱导的单核细胞趋化蛋白-1（MCP-1）、血管细胞粘附分子-1（VCAM-1）和E-选择素在HEC中的上调。Vasostatin-1通过下调巨噬细胞核因子-κ B（NF-κ B B）抑制炎症M1表型和LPS诱导的白细胞介素-6（IL-6）分泌。Vasostatin-1抑制氧化低密度脂蛋白（oxLDL）诱导的泡沫细胞形成与酰基辅酶A：胆固醇酰基转移酶-1（ACAT-1）和CD 36下调和ATP结合盒转运蛋白A1（ABCA 1）上调巨噬细胞。在HASMCs中，vasostatin-1通过降低ERK 1/2和p38磷酸化抑制血管紧张素II（AngII）诱导的迁移和胶原蛋白-3和纤连蛋白表达，但通过增加Akt和JNK磷酸化增加弹性蛋白表达和基质金属蛋白酶（MMP）-2和MMP-9活性。Vasostatin-1对HASMCs的增殖和凋亡无影响。在ApoE（-/-）小鼠中，血管抑素-1输注4周可抑制主动脉粥样硬化病变的发展，并降低斑块内炎症、巨噬细胞浸润和SMC含量以及血糖水平。这些结果表明vasostatin-1对动脉粥样硬化形成的抑制作用。本研究提供了第一个证据表明，血管抑素-1可能作为一个新的治疗动脉粥样硬化的目标。
Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE(-/-)) mice. Vasostatin-1 was expressed around Monckeberg's medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-KB (NF-kappa B) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE(-/-) mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.