RESUMO
Adipocytokine chemerin is a biologically active molecule secreted from adipose tissue. Chemerin elicits a variety of functions via chemokine-like receptor 1 (CMKLR1). The cardiovascular center in brain that regulates blood pressure (BP) is involved in pathophysiology of systemic hypertension. Thus, we explored the roles of brain chemerin/CMKLR1 on regulation of BP in spontaneously hypertensive rats (SHR). For this aim, we examined effects of intracerebroventricular (i.c.v.) injection of CMKLR1 small interfering (si)RNA on both systemic BP as measured by tail cuff system and protein expression in paraventricular nucleus (PVN) of SHR as determined by Western blotting. We also examined both central and peripheral protein expression of chemerin by Western blotting. Systolic BP of SHR but not normotensive Wistar Kyoto rats (WKY) was decreased by CMKLR1 siRNA. The decrease of BP by CMKLR1 siRNA persisted for 3 days. Protein expression of CMKLR1 in PVN of SHR tended to be increased compared with WKY, which was suppressed by CMKLR1 siRNA. Protein expression of chemerin in brain, peripheral plasma, and adipose tissue was not different between WKY and SHR. In summary, we for the first time revealed that the increased protein expression of CMKLR1 in PVN is at least partly responsible for systemic hypertension in SHR.
Assuntos
Regulação da Expressão Gênica , Hipertensão/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Quimiocinas/biossíntese , Animais , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Chemerin is an adipocytokine involved in inflammation and lipid metabolism via G protein-coupled receptor, chemokine-like receptor (CMKLR)1. Since the important nuclei regulating pressure (BP) exist in the brain, we examined the effects of acute intracerebroventricular (i.c.v.) injection of chemerin-9 on systemic BP and explored underlying mechanisms. We examined the effects of acute i.c.v. injection of chemerin-9 (10 nmol/head) on systemic BP by a carotid cannulation method in the control or CMKLR1 small interfering (si) RNA-treated Wistar rats (0.04 nmol, 3 days, i.c.v.). We examined protein expression of CMKLR1 around brain ventricles by Western blotting. We examined the effects of acute i.c.v. injection of chemerin-9 on serum adrenaline by a high performance liquid chromatography. In the control siRNA-treated rats, chemerin-9 significantly increased mean BP, which reached a peak at 2 to 4 min after injection. On the other hand, in the CMKLR1 siRNA-treated rats, chemerin-9 did not affect the mean BP. Protein expression of CMKLR1 specifically in subfornical organ (SFO) and paraventricular nucleus (PVN) from the CMKLR1 siRNA-treated rats decreased compared with the control siRNA-treated rats. In the control siRNA-treated rats, chemerin-9 increased serum adrenaline level. On the other hand, in the CMKLR1 siRNA-treated rats, chemerin-9 did not affect the serum adrenaline level. Further, pretreatment with prazosin, an α-adrenaline receptor blocker, significantly prevented the pressor responses induced by chemerin-9. In summary, we for the first time demonstrated that chemerin-9 stimulates the sympathetic nerves via CMKLR1 perhaps expressed in SFO and PVN, which leads to an increase in systemic BP.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Quimiocinas/administração & dosagem , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Epinefrina/sangue , Inflamação/metabolismo , Infusões Intraventriculares , Masculino , Prazosina/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Sistema Nervoso Simpático/metabolismoRESUMO
Chemerin is an adipocytokine whose concentration in blood correlates positively with blood pressure (BP). We have recently revealed that acute intracerebroventricular (i.c.v.) injection of chemerin-9, an active fragment of human chemerin, increased systemic BP in normal Wistar rats, suggesting that chemerin is involved in the central nervous control of peripheral BP. After secreted as an inactive form as prochemerin, a mature form of active chemerin is produced through the cleavage of its carboxyl (C)-terminus by proteases. Although the activity of cleaved products of chemerin has been examined in vitro, in vivo effects remained to be elusive. In order to explore them, we performed acute i.c.v. injection of mouse chemerin-9 (mChemerin-9; 148F-156S), mouse chemerin-8 (mChemerin-8; 148F-155F), and mouse chemerin-7 (mChemerin-7; 148F-154A) into Wistar rats, and examined the effects on systemic BP. After chemerin fragment (1-30 nmol/head, i.c.v.) was cumulatively administered, systemic BP was measured by a cannulation method under an isoflurane anesthesia. mChemerin-9 but not mChemerin-8 and -7 induced a pressor response, which was concentration-dependent. In conclusion, we for the first time demonstrated that mChemerin-9 that corresponds to the C-terminal nine amino acids of active mouse chemerin156S increased systemic BP in rats, and also that chemerin fragments showed different effects on systemic BP dependent on how their C-terminus was cleaved.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Isoflurano , Adipocinas , Aminoácidos , Animais , Pressão Sanguínea , Quimiocinas , Humanos , Camundongos , Peptídeo Hidrolases , Ratos , Ratos WistarRESUMO
Since chemerin is an adipocytokine whose concentration in blood increases in the subjects with various cardiac diseases, chemerin may be involved in pathogenesis of cardiac diseases. In the present study, we examined the effects of chemerin-9, an active fragment of chemerin, on functions of cardiac fibroblasts, which are involved in pathophysiology of cardiac diseases. Primary cardiac fibroblasts were enzymatically isolated from adult male Wistar rats. Migration of cardiac fibroblasts was measured by a Boyden chamber assay and a scratch assay. Phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was measured by Western blotting. Reactive oxygen species (ROS) production was measured by 2',7'-dichlorodihydrofluoresein staining. Chemerin-9 significantly stimulated migration in cardiac fibroblasts. Chemerin-9 significantly stimulated phosphorylation of Akt and ERK as well as ROS production. An Akt pathway inhibitor, LY294002, an ERK pathway inhibitor, PD98059, an antagonist of chemokine-like receptor 1 (CMKLR1), 2-(α-Napththoyl) ethyltrimethylammonium iodide, or an antioxidant, N-acetyl-L-cysteine prevented the migration induced by chemerin-9. In summary, we for the first time revealed that chemerin-9 stimulates migration perhaps through the ROS-dependent activation of Akt and ERK via CMKLR1 in cardiac fibroblasts. It is proposed that chemerin plays a role in the pathogenesis of cardiac diseases.