Ghrelin and obestatin modulate early atherogenic processes on cells: enhancement of monocyte adhesion and oxidized low-density lipoprotein binding.

Emerging evidence indicates the potential involvement of ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, in low-grade inflammatory diseases such as obesity and atherosclerosis. The goal of the present study was to use cell culture models to investigate the influences of ghrelin and obestatin in processes participating in atherogenesis. We studied monocyte adhesion, monocyte chemoattractant protein-1, and adhesion molecule expression on endothelial cells as well as binding of oxidized low-density lipoprotein (LDL) and acetylated LDL to macrophages. Ghrelin treatment increased adhesion of calcein-labeled THP-1 monocytes to EA.hy 926 endothelial cells. Simultaneously, ghrelin increased the expression of intercellular adhesion molecule-1 measured by quantitative reverse transcriptase polymerase chain reaction. Tumor necrosis factor-alpha stimulation together with ghrelin treatment decreased both monocyte adhesion and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression and, together with obestatin treatment, decreased vascular cell adhesion molecule-1 expression. Finally, ghrelin and obestatin increased binding of oxidized LDL to thioglycollate-elicited mouse peritoneal macrophages. No changes were observed in the uptake of acetylated LDL by mouse J774.A1 macrophages after exposure to ghrelin or obestatin. In conclusion, we found 3 lines of in vitro evidence supporting proatherogenic properties of ghrelin in the early stages of the disease. However, in the presence of tumor necrosis factor-alpha stimulation, opposite effects of ghrelin were observed, suggesting that ghrelin may also have an anti-inflammatory role in the presence of increased inflammation, for example, during the more progressed phases of atherogenesis.

The expression of human resistin in different leucocyte lineages is modulated by LPS and TNFalpha.

OBJECTIVE: Human resistin has been linked to several inflammatory diseases such as atherosclerosis. This study aimed to clarify the expression of resistin in different inflammatory cells and its effect on endothelial cells. RESULTS: In this study, RNA and protein expression of resistin were detected in human primary neutrophils, monocytes, and T cells as well as in human Jurkat T cells, RPMI-8226 B cells, monocytic U937, and myeloblastic HL-60 cell lines. The highest resistin protein and mRNA level were detected in neutrophils, primary monocytes, and monocytic U937 cells. The RNA expression of resistin was upregulated both in neutrophils and in U937 cells after exposure to LPS. Also TNFalpha induced resistin RNA expression in neutrophils, U937, T-lymphocytic Jurkat cells, and B-lymphocytic RPMI-8226 cells. The RNA and protein expression of resistin decreased as the monocytic U937 cells differentiated into macrophage-like cells. In endothelial EA.hy 926 cells, resistin increased the expression of MCP-1 and PECAM-1 and adhesion of monocytes to endothelial cells. CONCLUSIONS: The wide-ranging expression of resistin in white blood cells and the upregulation of its expression by inflammatory reagents LPS and TNFalpha support the fact that increased resistin could be involved in several inflammatory diseases.

Estrogen replacement therapy decreases plasma adiponectin but not resistin in postmenopausal women.

The effects of estrogen replacement therapy (ERT) to cardiovascular disease risk are still unclear. Low adiponectin and high resistin plasma concentrations are reported to be associated with atherosclerosis. However, it is not known how ERT affects plasma adiponectin and resistin concentrations. Seventy-three hysterectomized, nondiabetic, postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate or transdermal 17beta-estradiol gel for 6 months. Biochemical measurements were determined from samples taken before and after the therapy. Peroral estradiol valerate therapy decreased adiponectin concentrations from 13.6 to 11.6 mg/L (P = .008), whereas transdermal 17beta-estradiol gel had no effect (12.7 vs 12.2 mg/L). Neither treatment changed the resistin concentrations significantly. Plasma concentrations of estradiol and estrone did not correlate with adiponectin or resistin concentrations before or after therapy. The change in adiponectin concentration correlated significantly with the changes in waist-hip ratio, very low-density lipoprotein triglycerides, and insulin-like growth factor 1 in the peroral estradiol valerate group. The changes in these variables and the change in estradiol concentration explained 43.1% (P = .001) of the variability in the change of plasma adiponectin, the change in very low-density lipoprotein triglycerides being the strongest determinant (beta = -.407, P = .011). The results show that peroral ERT can decrease plasma adiponectin levels. However, ERT does not seem to influence plasma resistin concentrations.

Genetic variants at the resistin locus are associated with the plasma resistin concentration and cardiovascular risk factors.

OBJECTIVE: To examine the relation of the single nucleotide polymorphisms (SNPs) of the resistin gene on the plasma resistin concentration and cardiovascular risk factors. METHODS AND RESULTS: Plasma resistin concentrations were measured and SNP -420C>G, +157C>T, and +299G>A genotyped in our Finnish population-based cohort. Association analyses were performed in the control group of the cohort (n=515). In addition, the hypertension group (n=505), representing a high-risk group, was analyzed for these SNP's and the frequencies were compared with the low-risk control group. Resistin concentration differed significantly between the SNP genotypes, the common homozygotes having the lowest concentration in every SNP (p<0.01). After adjustment for age, sex, and BMI SNP -420C-C homozygotes had the lowest IGFBP-1 (p=0.001), the highest GHbA1c (p=0.028) in all the subjects and the lowest quick index (p<0.001) and the highest insulin (p<0.001) among female subjects of the control cohort. Plasma triglycerides were the lowest among G-G homozygotes (p=0.006). In addition, the SNP -420C allele was more frequent among hypertensive than control cohort (p=0.018). CONCLUSIONS: The results imply that genetic variation seems to have a role in the determination of plasma resistin level. SNP -420C-C homozygozity status seems to be associated with more deleterious metabolic profile.

High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes.

OBJECTIVES: Resistin is a newly described hormone with a suggested role in insulin resistance. In humans, inflammatory cells seem to be the major source of resistin. The aim of this study was to find out whether plasma resistin concentration associates with carotid artery atherosclerosis and the risk factors of atherosclerosis. METHODS: Plasma resistin concentrations were measured in 525 Finnish middle-aged subjects among our population-based cohort. Intima-media thickness was measured from the internal carotid artery, the bifurcation enlargement, and the common carotid artery. RESULTS: Among all the subjects, the median resistin concentration was 7.07 ng/ml (interquartile range, 5.82-8.84), women having higher levels than men (P < 0.001) with median values of 7.56 ng/ml (6.18-9.19) and 6.67 ng/ml (5.63-8.31), respectively. Resistin level correlated negatively with mean intima-media thickness, internal carotid artery, and common carotid artery, but the association did not remain significant after adjustments. Plasma resistin concentration was associated positively with leukocytes (P < 0.001), highly sensitive C-reactive protein (P = 0.009), and IGF binding protein 1 (P < 0.001), but not with plasma insulin or glucose levels in analysis of covariance after adjustments for age, sex, and body mass index. CONCLUSIONS: The results imply that inflammatory factors are more important in the determination of plasma resistin concentration than plasma insulin or glucose values. Resistin is associated with proatherogenic inflammatory markers but not independently with early atherosclerosis.