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

Abstract

BackgroundKisspeptin‐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 ResultsWe 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.ConclusionsOur 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.

Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines

“…In human aortic smooth muscle cells, KP-10 significantly suppressed angiotensin II-induced migration and proliferation, but increased apoptosis and the activities of MMP-2 and MMP-9 via the upregulation of extracellular signal-regulated kinase 1 and 2, p38, Bax, and caspase-3. MMP-2 increases cancer cell migration by degrading extracellular collagen tissue (39).…”

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

“…However, anatomic considerations preclude this as a likely explanation for the aforementioned observations in the aorta and superior mesenteric artery and for arterioles not arranged in parallel with venules. A third possibility is release of inflammatory mediators the produce hyperreactive vasoconstrictor responses that limit NO-dependent dilation in arterial vessels, as has been observed in atherosclerotic plaques (Sato, Shirai, Hontani, Shinooka, Hasegawa, Kichise, et al, 2017). Similar responses have been suggested to play a role in vascular smooth muscle hyperreactivity associated with variant angina (Lanza & Maseri, 2000).…”

Sympathetic innervation regulates macrophage activity in rats with polycystic ovary

“…It has been shown that neuropeptides such as NGF and kiss act as regulators of reproductive functions and can influence both the neuronal cell function (at the level of the central nervous system and peripheral system) and the inflammatory response (Sato et al 2017, Minnone et al 2017. Most inflammatory cells produce NGF and express TrkA.…”

“…Although the immunomodulatory effects of kiss have not been fully explored yet, it has been reported that the levels of this peptide in plasma rise abruptly during normal pregnancy and have direct effects on the regulatory subpopulations of T lymphocytes (Gorbunova & Shirshev 2016). On the other hand, it has been demonstrated that Kiss mRNA expression is increased by TNFα, IL-6, MCP-1 and VCAM-1 in human endothelial cells, and thus, accelerates atherogenesis by enhancing the inflammatory responses (Sato et al 2017). PCOS is associated with chronic low-grade inflammation and predisposition to hemostatic and atherosclerotic complications (Carvalho et al 2017), accompanied by high plasma levels of kiss (Chen et al 2010).…”