Protein quality control systems in hypertrophic cardiomyopathy:pathogenesis and treatment potential

Hypertrophic cardiomyopathy(HCM)is genetic cardiomyopathy with the risk of sudden death characterized by abnormal sarcomere protein.^([1])Although some pathogenic genes related to HCM have been reported,^([2])the disease phenotype and pathogenesis cannot be fully elucidated,which brings great difficulties to the diagnosis and treatment of HCM,especially the exploration of HCM treatment strategies.

Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-lnduced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells

Background：Oxidized low-density lipoprotein （ox-LDL）-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase （PERK）/eukaryotic translation initiation factor 2α-subunit （eIF2α）/CCAAT/enhancer-binding protein homologous protein （CHOP） endoplasmic reticulum （ER） stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells.Methods：Human umbilical vein endothelial cells （HUVECs） were treated with simvastatin （0.1, 0.5, or 2.5 μmol/L） or DEVD-CHO （selective inhibitor of caspase-3, 100 μmol/L） for 1 h before the addition of ox-LDL （100 μg/ml） and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance （ANOVA） followed by post hoc pairwise comparisons using Tukey’s tests. A value of P 〈 0.05 was considered statistically significant.Results：Exposure of HUVECs to ox-LDL resulted in a significant increase in apoptosis （31.9% vs. 4.9%, P 〈 0.05）. Simvastatin （0.1, 0.5, and 2.5 μmol/L） led to a suppression of ox-LDL-induced apoptosis （28.0%, 24.7%, and 13.8%, F = 15.039, all P 〈 0.05, compared with control group）. Ox-LDL significantly increased the expression of PERK （499.5%, P 〈 0.05） and phosphorylation of eIF2α （451.6%, P 〈 0.05）, if both of which in the control groups were considered as 100%. Simvastatin treatment （0.1, 0.5, and 2.5 μmol/L） blunted ox-LDL-induced expression of PERK （407.8%, 339.1%, and 187.5%, F = 10.121, all P 〈 0.05, compared with control group） and phosphorylation of eIF2α （407.8%, 339.1%, 187.5%, F = 11.430, all P 〈 0.05, compared with control group）. In contrast, DEVD-CHO treatment had no significant effect on ox-LDL-induced expression of PERK （486.4%） and phosphorylation of eIF2α （418.8%）. Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment.Conclusions：This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.

Synthesis and Characterization of Fluorinated Polyurethane Containing Carborane in the Main Chain: Thermal, Mechanical and Chemical Resistance Properties

In this study, two fluorinated polyurethanes（FPU） containing carborane groups in the main chains were firstly designed and synthesized via the reaction of hexamethylene diisocyanate trimer（HDI trimer） with fluorinated polyesters（CFPETs） having hydroxyl-terminated carborane groups at room temperature. The structures of carborane fluorinated polyesters（CFPETs） and polyurethanes（CFPUs） were characterized by gel permeation chromatography（GPC）, Fourier transform infrared（FTIR） spectroscopy and nuclear magnetic resonance（NMR） measurements. The thermal stability, mechanical properties, Shore A hardness, solvent resistance and acid-alkali resistance of the carborane fluorinated polyurethane films were also studied. Thermogravimetric analysis（TGA） tests manifested that the introduction of carborane groups into the main chain of fluorinated polyurethane endowed the obtained fluorinated polyurethane with excellent thermal stability. The thermal decomposition temperature of carborane fluorinated polyurethane（CFPU） increased by 190 °C compared with that of the carborane-free fluorinated polyurethane（FPU）. Even at 800 °C, CFPU showed the char yield of 66.5%, which was higher than that of FPU（34.3%）. The carborane-containing fluorinated polyurethanes also showed excellent chemical resistance and prominent mechanical property even after the cured films being immersed into Jet aircraft oil or 37% HCl for 168 h or at high temperature（700 °C）. It is found that the structural characteristics of carborane group and the compacted structure of CFPU effectively improve the thermal stability, mechanical property, solvent resistance and acid-alkali resistance of the carborane-free fluorinated polyurethane. These excellent properties make CFPU as the useful raw materials to prepare the high temperature resistant coatings or adhesives for automotive engines, engine or fuel tank of aircraft and other equipment working in high-temperature or high concentrations of acid-alkali environments.