A natural squamosamide derivative FLZ inhibits homocysteine-induced rat brain microvascular endothelial cells dysfunction.
Hyperhomocysteinemia is believed to induce endothelial dysfunction, which is an independent risk factor for atherosclerosis and vascular diseases. Compound FLZ is a novel synthetic squamosamide cyclic analog with several phenolic hydroxy groups, and exhibits strong anti-oxidative and neuroprotective activities in Alzheimer's and Parkinson's models. In the present study, we examined the actions of FLZ against homocysteine-induced injury to primary cultured rat brain microvascular endothelial cell (rBMECs). Cell survival was measured by MTT assay. Cell nuclei were observed by Hoechst 33342 staining. Senescent cells were detected by senescence-associated β-galactosidase (SA-β-gal) staining. Reactive oxygen species (ROS) were measured by 2',7'-dichlorofluorescein (DCF) fluorescent microscopy. Homocysteine-induced expression of NF-κB, p53, Noxa and Fas, and the release of mitochondrial cytochrome c, were measured by Western blotting. We found that FLZ treatment antagonized homocysteine-induced cell death and apoptosis and increased numbers of senescent cells. These changes were correlated with decreased ROS accumulation. FLZ treatment inhibited activation of NF-κB, the upregulation of p53, Noxa, and Fas, and blocked mitochondrial cytochrome c release. These data suggest that FLZ has a protective action against homocysteine-induced toxicity in rBMECs, suggesting that FLZ may have therapeutic potential for the prevention of cardiovascular diseases.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 2, Xiannongtan Road, Beijing 100050, China.
Rui-xia
RX
Kang
Jian-jun
JJ
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000473:pathology / Q000503:physiopathology*; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013194:Staining and Labeling; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D044482:Benzeneacetamides; D016328:NF-kappa B; D010636:Phenols; C539472:Pmaip1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D006710:Homocysteine; C084439:squamosamide; D045304:Cytochromes c