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J Am Heart Assoc. 2017 Apr 14;6(4). pii: e005790. doi: 10.1161/JAHA.117.005790.

Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist.

Author information

1
Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan ksato@toyaku.ac.jp.
2
Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
3
Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan.
4
Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
5
Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

atherosclerosis; endothelial cell; kisspeptin‐10; macrophage; plaque instability; smooth muscle cell; vasoconstriction

PMID:
28411243
PMCID:
PMC5533042
DOI:
10.1161/JAHA.117.005790
[Indexed for MEDLINE]
Free PMC Article

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