Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes  

作　　者：Tian-tian Liu Huan-huan Xu Ze-juan Liu He-ping Zhang Hai-tao Zhou Zhi-xiang Zhu Zhi-qiang Wang Jing-yi Xue Qiang Li Yi Ma Hong-jie You Da-li Luo 

机构地区：[1]Department of Pharmacology,Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance,Capital Medical University,Beijing,100069,China [2]Beijing Friendship Hospital,The Affiliated Hospital of Capital Medical University,Beijing,100065,China [3]National Cancer Center,National Clinical Research Center for Cancer,Cancer Hospital,and Peaking Union Medical College,Chinese Academy of Medical Sciences,Beijing,100021,China

出　　处：《Acta Pharmacologica Sinica》2023年第12期2492-2503,共12页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(81570206 and 81970197);the Scientific Research Key Program of Beijing Municipal Commission of Education(KZ201710025023).

摘　　要：Endothelial dysfunction,a central hallmark of cardiovascular pathogenesis in diabetes mellitus,is characterized by impaired endothelial nitric oxide synthase(eNOS)and NO bioavailability.However,the underlying mechanisms remain unclear.Here in this study,we aimed to identify the role of calmodulin(CaM)in diabetic eNOS dysfunction.Human umbilical vein endothelial cells and murine endothelial progenitor cells(EPCs)treated with high glucose(HG)exhibited downregulated CaM mRNA/protein and vascular endothelial growth factor(VEGF)expression with impeded eNOS phosphorylation and cell migration/tube formation.These perturbations were reduplicated in CALM1-knockdown cells but prevented in CALM1-overexpressing cells.EPCs from type 2 diabetes animals behaved similarly to HG-treated normal EPCs,which could be rescued by CALM1-gene transduction.Consistently,diabetic animals displayed impaired eNOS phosphorylation,endothelium-dependent dilation,and CaM expression in the aorta,as well as deficient physical interaction of CaM and eNOS in the gastrocnemius.Local CALM1 gene delivery into a diabetic mouse ischemic hindlimb improved the blunted limb blood perfusion and gastrocnemius angiogenesis,and foot injuries.Diabetic patients showed insufficient foot microvascular autoregulation,eNOS phosphorylation,and NO production with downregulated CaM expression in the arterial endothelium,and abnormal CALM1 transcription in genome-wide sequencing analysis.Therefore,our findings demonstrated that downregulated CaM expression is responsible for endothelium dysfunction and angiogenesis impairment in diabetes,and provided a novel mechanism and target to protect against diabetic endothelial injury.

关 键 词：diabetes mellitus CALMODULIN endothelial nitric oxide synthase angiogenesis endothelial progenitor cell hind limb ischemia 

分 类 号：R734.2[医药卫生—肿瘤]