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Kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis in adult male rats following central and peripheral administration
Kisspeptin is the peptide product of the KiSS-1 gene and endogenous agonist for the GPR54 receptor. The kisspeptin/GPR54 system has recently been suggested as a key regulator of the reproductive system. GPR54 deficient mice have abnormal sexual development and low circulating gonadotrophins and in humans, GPR54 mutations have been shown to cause hypogonadotrophic hypogonadism. Thus, GPR54 appears to be essential for normal gonadotrophin secretion and the regulation of puberty. To further investigate the role of kisspeptin in the hypothalamic-pituitary-gonadal (HPG) axis, we examined the effect of intracerebroventricular (i.c.v.) and peripheral administration of the active kisspeptin fragment, kisspeptin-10, on circulating gonadotrophins and total testosterone levels in adult male rats. The effect of kisspeptin-10 in vitro on the release of hypothalamic peptides from hypothalamic explants and gonadotrophins from anterior pituitary fragments was also determined. The i.c.v. administration of kisspeptin-10 dose-dependently increased plasma luteinizing hormone (LH) and increased plasma follicle stimulating hormone (FSH) and total testosterone at 60 minutes post-injection. In a separate investigation into the time course of this response, i.c.v. administered kisspeptin-10 (3 nanomoles) significantly increased plasma LH at 10, 20 and 60 minutes, FSH at 60 minutes and total testosterone at 20 and 60 minutes post-injection. Kisspeptin-10 stimulated the release of luteinizing hormone-releasing hormone (LHRH) from in vitro hypothalamic explants. Peripheral administration of kisspeptin-10 increased plasma LH, FSH and total testosterone. However, doses of 100-1000 nanomolar kisspeptin-10 had no effect on LH or FSH release from pituitary fragments. These results demonstrate that kisspeptin potently stimulates the HPG axis, and these effects are likely to be mediated via the hypothalamic LHRH system.
Treatment with KP, which stimulates insulin secretion through activation of the PLC pathway, resulted in a significant, additional increase in NAD(P)H compared to untreated control islets over a range of glucose concentrations (p<0.01, Fig. 1B).
Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway
BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.
Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis
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A potent vasoconstrictor kisspeptin-10 (KP-10) and its receptor GPR54 have currently received much attention with respect to atherosclerosis.
Both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury.
KP-10 contributes to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques.
GPR54 antagonists are useful for the prevention and treatment of atherosclerosis.
The KP-10/GPR54 system may serve as a promising biomarker and therapeutic target for atherosclerotic diseases.
Kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention with respect to atherosclerosis, since both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury. The present review introduces the emerging roles of the KP-10/GPR54 system in atherosclerosis.
KP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs), and induces senescence in HUVECs. KP-10 increases adhesion of human monocytes to HUVECs. KP-10 also stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs. KP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation, however, it enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3. Four-week-infusion of KP-10 into Apoe−/- mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation, also, it decreases intraplaque vascular smooth muscle cell content. Proatherosclerotic effects of endogenous and exogenous KP-10 were completely attenuated upon infusion of P234, a GPR54 antagonist, in Apoe−/− mice.