机构地区:[1]School of Public Health and Hongqiao International Institute of Medicine,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China [2]Institute for Developmental and Regenerative Cardiovascular Medicine,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,200092,China [3]School of Medicine,Shanghai University,Shanghai,200444,China [4]Department of Pharmacy,Second Affiliated Hospital of Naval Medical University,Shanghai,200003,China [5]Department of Pharmacology,School of Basic Medical Sciences,Peking University and Beijing Key Laboratory of Tumor Systems Biology,Peking University,Beijing,100191,China
出 处:《Acta Pharmacologica Sinica》2023年第1期44-57,共14页中国药理学报(英文版)
基 金:This work was supported by grants from the Ministry of Science and Technology of China (2021YFA0804803);the National Natural Science Foundation of China (81870189,82070266,81900243,81930012,81730013,92168120 and 81974506);the Beijing Natural Science Foundation(Z200019).
摘 要:It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications.Endothelial progenitor cell(EPC)dysfunction is a key contributor to diabetic vascular complications.In the present study we evaluated whether low-dose nifedipine could rescue impaired EPC-mediated angiogenesis and prevent cardiovascular complications in diabetic mice.Diabetes was induced in mice by five consecutive injections of streptozotocin(STZ,60 mg·kg−1·d−1,i.p.).Diabetic mice were treated with low-dose nifedipine(1.5 mg·kg−1·d−1,i.g.)for six weeks.Then,circulating EPCs in the peripheral blood were quantified,and bone marrow-derived EPCs(BM-EPCs)were prepared.We showed that administration of low-dose nifedipine significantly increased circulating EPCs,improved BM-EPCs function,promoted angiogenesis,and reduced the cerebral ischemic injury in diabetic mice.Furthermore,we found that low-dose nifedipine significantly increased endothelial nitric oxide synthase(eNOS)expression and intracellular NO levels,and decreased the levels of intracellular O2.−and thrombospondin-1/2(TSP-1/2,a potent angiogenesis inhibitor)in BM-EPCs of diabetic mice.In cultured BM-EPCs,co-treatment with nifedipine(0.1,1μM)dose-dependently protected against high-glucose-induced impairment of migration,and suppressed high-glucose-induced TSP-1 secretion and superoxide overproduction.In mice with middle cerebral artery occlusion,intravenous injection of diabetic BM-EPCs treated with nifedipine displayed a greater ability to promote local angiogenesis and reduce cerebral ischemic injury compared to injection of diabetic BM-EPCs treated with vehicle,and the donor-derived BM-EPCs homed to the recipient ischemic brain.In conclusion,low-dose nifedipine can enhance EPCs’angiogenic potential and protect against cerebral ischemic injury in diabetic mice.It is implied that chronic treatment with low-dose nifedipine may be a safe and economic manner to prevent ischemic diseases(including stroke)in diabetes.
关 键 词:diabetes NIFEDIPINE endothelial progenitor cells ANGIOGENESIS cerebral ischemia THROMBOSPONDINS
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