Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.

CXCL16 deficiency attenuates STZ-induced diabetic nephropathy in mice / 中国病理生理杂志

AIM:To explore the effect of CXCL16 deficiency on streptozocin ( STZ)-induced diabetic nephrop-athy in mice.METHODS:CXCL16 knockout ( C16 KO) mice (8 years old) were used to build up diabetes model by treating with STZ.Age-and gender-matched wild-type ( WT) C57BL/6J mice treated with STZ were used as control.All mice were fed with chow diets for 12 weeks, and the development of diabetic nephropathy was evaluated.RESULTS:Compared with the WT mice treated with STZ, C16 KO mice treated with STZ presented lower fasting glucose levels and better glucose tolerance power.C16 KO mice treated with STZ also had lower urine protein levels and smaller areas of glo-merular injury as compared with WT mice treated with STZ.Furthermore, CXCL16 deficiency decreased the contents of re-nal reactive oxygen species ( ROS) , malondialdehyde ( MDA) and oxidized low-density lipoprotein ( ox-LDL) and the mR-NA expression of lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1), and attenuated the expression of renal in-flammatory factors including tumor necrosis factor α( TNF-α) and interleukin 6 ( IL-6) , as well as chemokines including intercellular cell adhesion molecular 1 (ICAM-1) and chemokine C-X-C motif ligand 1 (CXCL1).CONCLUSION:CX-CL16 deficiency obviously inhibits the development of STZ-induced diabetic nephropathy in mice.

Effects of Sonic Hedgehog pathway on apoptosis of endothelial cells / 中华风湿病学杂志

Objective To investigate Smoothened (Smo) expression in endothelial cells of synovial tissues in active rheumatoid arthritis (RA),and the expression of Sonic Hedgehog (Shh) signaling pathwayassociated factors after TNF-α treatment in EA.hy926 cells,and the effects of specific inhibitor of Smo (cyclopamine) on the apoptosis of EA.hy926 cells.Methods The Smo expression in endothelial cells in synovial tissue from 4 RA patients and 4 patients with traumatic or meniscal injury (with no arthritis,act as control group) were detected by immunohistochemistry assay.EA.hy926 cells were treated with different concentrations of TNF-α or TNF-α together with different concentrations of cyclopamine,and Shh,Ptch1,Smo,Gli1 mRNA expression levels were detected by real time-PCR.EA.hy926 cells were co-cultured with three different concentrations of cyclopamine for 24 hours before the addition of TNF-α and ActinomycinD (ActD).The cell survival rate was detected using CCK-8,and the population of apoptotic cells was detected using a flow cytometry.T-test and one-way ANOVA were used for statistical analysis.Results The positive expression rate of Smo in endothelial cells of synovial tissue in RA group was (81±23)％,which was higher than that in the control group (20±17)％ (P＜0.05).After being treated with TNF-α,the expressions of Shh and Smo mRNA in EA.hy926 cells increased,while the expression of Gli1 mRNA decreased (P＜0.05),and the expression of Ptch1 mRNA did not change significantly (P＞0.05).The expressions of Shh,Smo and Gli1 mRNA were down-regulated (P＜0.05).EA.hy926 cells treated with different concentrations of cyclopamine (2,4 and 8 μmol/L) showed a significant decrease in cell viability,in cell survival rates (57±6)％,(44±8)％ and (32±5)％ compared with that of TNF-α/ActD group (64±6)％ (P＜0.05),and cell apoptosis rates [(12.4±3.3)％,(14.5±2.7)％ (15.7±2.4)％] compared with that of TNF-α/ActD group (7.1±1.3)％ (P＜0.05).Conclusion Shh pathway is activated in endothelial cells of synovial tissue in active RA.The apoptosis in endothelial cells is promoted after cyclopamine treatment.Shh pathway may play an important role in the antiapoptotic regulatory mechanism of endothelial cells.

The cardiac protection of non-mitogenic human fibroblast growth factor on cardiomyocytes treated with hydrogen peroxide in vitro / 中国病理生理杂志

AIM: To study the protective effects of n on -mitogenic human fibroblast growth factor (nm-haFGF) on cardiomyocytes injured b y reactive oxygen free radicals. METHODS: The cardiomyocytes were isolated from neonatal SD mouse by trypsin digestion. The cardiomyocytes injury model was established by expos ing the cells to hydrogen peroxide (H 2O 2), and the injury status in cardiomy ocytes were evaluated by examining the cellular viability, measuring cell apopto sis and observing the change of cellular morphology. nm-haFGF was added to the c ulture medium, and the changes of cellular viability, superoxide dismutase (SOD) , malondialdehyde (MDA) and celluar apoptosis were observed. RESULTS: A dose-dependence relation between the concentration of H 2O 2 and the cardiomyocytes injury was observed. 10-80 ?g/L nm-haFGF dose -dependently increased cardiomyocyte viability and the general SOD activity, as well as decreased the content of MDA and the quantity of cardiomyocyte apoptosis . CONCLUSION: The higher the concentration of H 2O 2, the mor e serious the cardiomyocyte injury. nm-haFGF may have a good protective effects on cardiomyocytes treated with H 2O 2.