Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist.
Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist.
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DOI：
10.1161/jaha.117.005790
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发表时间：
2017-04-14
影响因子：
5.4
通讯作者：
Watanabe T
中科院分区：
文献类型：
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作者：
Sato K;Shirai R;Hontani M;Shinooka R;Hasegawa A;Kichise T;Yamashita T;Yoshizawa H;Watanabe R;Matsuyama TA;Ishibashi-Ueda H;Koba S;Kobayashi Y;Hirano T;Watanabe T
Kisspeptin-10（KP-10）是一种有效的血管收缩剂和血管生成抑制剂，其受体GPR 54目前在先兆子痫方面受到了广泛关注。然而，目前尚不清楚KP-10是否会影响动脉粥样硬化形成。我们评价了KP-10对体外人脐静脉内皮细胞、人单核细胞源性巨噬细胞、人主动脉平滑肌细胞以及载脂蛋白E缺陷（ApoE−/−）小鼠体内动脉粥样硬化病变的影响。KP-10显著增加人单核细胞与人脐静脉内皮细胞的粘附，这被GPR 54拮抗剂P234预处理显著抑制。KP-10刺激人脐静脉内皮细胞中肿瘤坏死因子-α、白细胞介素-6、单核细胞趋化蛋白-1、细胞间粘附分子-1、血管粘附分子-1和E-选择素的mRNA表达。KP-10显著增强氧化低密度脂蛋白诱导的泡沫细胞形成，与人单核细胞衍生的巨噬细胞中CD 36和酰基辅酶A：胆固醇酰基转移酶-1的上调相关。在人主动脉平滑肌细胞中，KP-10显著抑制血管紧张素II诱导的迁移和增殖，但通过上调细胞外信号调节激酶1和2、p38、Bcl-2相关X蛋白和caspase-3，增强细胞凋亡和基质金属蛋白酶（MMP）-2和MMP-9的活性。向ApoE−/−小鼠输注KP-10 4周显著加速了主动脉粥样硬化病变的发展，单核细胞/巨噬细胞浸润和血管炎症增加，斑块内血管平滑肌细胞含量减少。内源性和外源性KP-10的促动脉粥样硬化作用通过在ApoE−/−小鼠中输注P234完全消除。我们的研究结果表明，KP-10可能有助于加速动脉粥样硬化斑块的进展和不稳定性，导致斑块破裂。GPR 54拮抗剂可用于预防和治疗动脉粥样硬化。因此，KP-10/GPR 54系统可能成为动脉粥样硬化疾病的新治疗靶点。
Kisspeptin‐10 (KP‐10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention in relation to pre‐eclampsia. However, it still remains unknown whether KP‐10 could affect atherogenesis. We evaluated the effects of KP‐10 on human umbilical vein endothelial cells, human monocyte‐derived macrophages, human aortic smooth muscle cells in vitro, and atherosclerotic lesions in apolipoprotein E–deficient (ApoE−/−) mice in vivo. KP‐10 significantly increased the adhesion of human monocytes to human umbilical vein endothelial cells, which was significantly inhibited by pretreatment with P234, a GPR54 antagonist. KP‐10 stimulated mRNA expression of tumor necrosis factor‐α, interleukin‐6, monocyte chemotactic protein‐1, intercellular adhesion molecule‐1, vascular adhesion molecule‐1, and E‐selectin in human umbilical vein endothelial cells. KP‐10 significantly enhanced oxidized low‐density lipoprotein–induced foam cell formation associated with upregulation of CD36 and acyl‐CoA:cholesterol acyltransferase‐1 in human monocyte‐derived macrophages. In human aortic smooth muscle cells, KP‐10 significantly suppressed angiotensin II–induced migration and proliferation, but enhanced apoptosis and activities of matrix metalloproteinase (MMP)‐2 and MMP‐9 by upregulation of extracellular signal‐regulated kinase 1 and 2, p38, Bcl‐2‐associated X protein, and caspase‐3. Four‐week‐infusion of KP‐10 into ApoE−/− mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation as well as decreased intraplaque vascular smooth muscle cells contents. Proatherosclerotic effects of endogenous and exogenous KP‐10 were completely canceled by P234 infusion in ApoE−/− mice. Our results suggest that KP‐10 may contribute to accelerate the progression and instability of atheromatous plaques, leading to plaque rupture. The GPR54 antagonist may be useful for prevention and treatment of atherosclerosis. Thus, the KP‐10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.