Celastrol attenuates adipokine resistin‐associated matrix interaction and migration of vascular smooth muscle cells

Obesity instigates various health problems such as atherosclerosis, diabetes, and cancer. Resistin, an adipose tissue‐specific secretory adipokine, operates endocrine functions through increasing insulin resistance. Vascular smooth muscle cells (SMC) migrate into the subendothelial space and proliferate, thereby contributing to neointimal formation in atherosclerosis and restenosis. The aim of this study was to elucidate whether celastrol obtained from Tripterygium wilfordii Hook, inhibited human aortic SMC migration. Celastrol capable of antagonizing inflammatory responses attenuated the resistin secretion from THP‐1‐derived macrophages. The macrophage‐conditioned media promoted SMC proliferation and MMP‐2 production, which was dampened by 10–100 nM celastrol. Celastrol encumbered the SMC migration in response to 50 ng/ml resistin, concomitant with the inhibition of induction of connective tissue growth factor and collagen I/IV. In addition, celastrol disabled human aortic SMC exposed to resistin from migrating. The resistin‐induced shedding of integrin β2/β3 expression was demoted by celastrol, thereby contributing to the inhibition of collagen matrix‐SMC interaction. Next, resistin‐induced Toll‐like receptor‐4 (TLR‐4) expression was abrogated by celastrol, indicating that TLR‐4 was the resistin signaling receptor that was blocked by celastrol. Collectively, these results demonstrate that anti‐inflammatory celastrol blunted the macrophage secretion of the adipokine resistin, and suppressed the SMC migration by disturbing the interaction between SMC and intimal collagen matrix. Therefore, celastrol may inhibit atherogenic migration of vascular SMC upon resistin loading by intimal macrophages within atherosclerotic lesions. J. Cell. Biochem. 114: 398–408, 2013. © 2012 Wiley Periodicals, Inc.     

Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15): a new marker of all‐cause mortality

Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15) is a member of the TGF‐b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC‐1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC‐1/GDF15 may be a marker of all‐cause mortality. To determine whether serum MIC‐1/GDF15 estimation is a predictor of all‐cause mortality, we examined a cohort of 876 male subjects aged 35–80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC‐1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same‐sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL‐6) and C‐reactive protein (CRP) available. Patients were followed for up to 14 years and had cause‐specific and all‐cause mortality determined. Serum MIC‐1/GDF15 levels predicted mortality in the all‐male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38–8.26). This finding was validated in the twin cohort. Serum MIC‐1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL‐6 and CRP. Additionally, serum MIC‐1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC‐1/GDF15 is a novel predictor of all‐cause mortality.