Abstract 17078: A Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability

Abstract

Background: Recently, there is a great deal of research interest regarding the role and effects of kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis expressed in vascular endothelial cells (ECs), in cardiovascular disease. However, it still remains unknown whether KP-10 could affect atherogenesis. Objective and Methods: We aimed to clarify the effects of KP-10 on atherosclerosis. We evaluated the effects of KP-10 on human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs) in vitro , and aortic lesions in ApoE -/- mice in vivo . Results: GPR54, a KP-10 receptor, was expressed at higher levels in human monocytes, macrophages, HASMCs, and HUVECs. KP-10 significantly suppressed the proliferation of EAhy.926 ECs. KP-10 significantly increased the adhesion of THP1 monocytes to HUVECs associated with increased endothelial expressions of IL-6, MCP-1, TNF-α, ICAM-1, VCAM-1, and E-selectin. KP-10 significantly enhanced oxidized low-density lipoprotein-induced foam cell formation associated with increased expressions of CD36 and acyl-CoA:cholesterol acyltransferase-1 in human monocyte-derived macrophages. KP-10 significantly suppressed the migration and proliferation of HASMCs with inducing apoptosis via AKT, p38, and bax upregulation, but significantly enhanced the activities of MMP-2 and MMP-9 in HASMCs. Four-week-infusion of KP-10 into ApoE -/- mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration. Conclusions: Our results indicate that KP-10 accelerates atherogenesis by enhancing EC inflammatory responses and macrophage foam cell formation, In addition, KP-10 suppresses EC proliferation, VSMC migration and proliferation, but enhances MMP-2 and MMP-9 activities in VSMCs, which may contribute to plaque instability, leading to plaque rupture. Thus, KP-10 may serve as a novel therapeutic target for acute coronary syndrome.