title: Benidipine, a dihydropyridine-calcium channel blocker, prevents lysophosphatidylcholine-induced injury and reactive oxygen species production in human aortic endothelial cells.
abstract: Lysophosphatidylcholine (lysoPC) is a component of oxidized low-density lipoproteins (oxLDLs), which play an important role in the pathogenesis of atherosclerosis. In this study, we examined whether benidipine hydrochloride (benidipine), a dihydropyridine-calcium channel blocker with antioxidant activity, prevents lysoPC (C 16:0)-induced injury of human aortic endothelial cells (HAEC). Treatment of HAECs with lysoPC changed cell morphology, decreased cell viability and induced DNA fragmentation, leading to apoptosis. Additionally, lysoPC species containing palmitoyl (C 16:0) or stearoyl (C 18:0), which are the major components of oxLDLs, stimulated reactive oxygen species (ROS) production and induced caspase-3/7-like activity in HAECs, but lysoPC species with short acyl chains did not affect either ROS production or caspase-3/7-like activity. Pretreatment with benidipine (0.3-3 micromol/L) for 24 h protected against lysoPC-induced cytotoxicity in the endothelial cells and the drug inhibited both lysoPC-stimulated ROS production and caspase-3/7-like activation with a similar potency. Since caspase-3/7 is involved in executing the apoptotic process, the reduction of the activity of this enzyme by benedipine may explain the anti-apoptotic effect of the drug. However, benidipine did not suppress lysoPC-induced phosphorylation of mitogen-activated protein kinases and Ca2+ influx in HAECs. These results suggest that the anti-oxidant properties of benidipine may be responsible for its ability to inhibit ROS production, resulting in reduced activation of caspase-3/7. In conclusion, benidipine suppresses lysoPC-induced endothelial dysfunction through inhibition of ROS production, which is due at least in part to its antioxidant effect, and not through the inhibition of L-type voltage-dependent calcium channels.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co. Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. masahiro.matsubara@kyowa.co.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsubara
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hasegawa
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008244:Lysophosphatidylcholines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008244:Lysophosphatidylcholines; D017382:Reactive Oxygen Species; C061004:benidipine; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases