项目来源
湖北省自然科学基金
项目主持人
李彩蓉
项目受资助机构
湖北科技学院
立项年度
2017
立项时间
未公开
项目编号
2017CFB410
项目级别
省级
研究期限
未知 / 未知
受资助金额
7.00万元
学科
人口与健康生物医药
学科代码
未公开
基金类别
未公开
关键词
酸敏感离子通道 ; PICK1 ; 糖尿病心肌病 ; 糖尿病 ; 钙离子 ; ASICs ; Diabetic Cardiomyopathy ; Diabetes ; Calcium Ion
参与者
蔡飞；张又枝；张如意；刘冉；程正
参与机构
未公开
项目标书摘要：糖尿病心肌病(DCM)是由糖尿病导致的心脏结构和功能障碍性疾病，胞内钙超载所致的细胞损伤是DCM产生的重要因素。本研究通过高糖高脂联合小剂量 STZ 腹腔注射建立 DCM 模型，以及体外高糖诱导 H9c2 心肌细胞损伤模型，采用小动物超声影像、免疫组化、膜片钳、钙离子成像和分生技术研究ASICs和PICK1在DCM发病中的作用，结果发现:①糖尿病大鼠心肌组织中PICK1蛋白含量随着病程进展而逐渐增加，抑制ASIC1a可改善大鼠心功能、减少血清肌酸激酶和乳酸脱氢酶的含量，减轻心肌损伤及细胞凋亡，在高糖环境下,PcTx1剂量依耐性的减轻高糖所致的细胞损伤;②抑制钠氢交换体1能改善糖尿病db/db小鼠心脏损伤，其机制可能与CAR改善高糖高脂和胰岛素抵抗，抗氧化应激能力及调节Calpain和AKT/GSK-3β蛋白有关;③不同浓度高脂(PA)作用于H9C2 心肌细胞会导致细胞凋亡，其原因可能与PA增加细胞活性氧的产生有关；洛利普兰对 PA 所致细胞脂毒性损伤具有保护作用，其保护机制可能与抑制细胞内氧化应激及细胞凋亡有关;④ METTL3依赖的m6ARNA甲基化修饰可能影响心肌内氧化还原动态平衡而介导DOX心肌毒性作用。该研究将为以ASICs 和 PICK1为靶点探讨糖尿病心肌病的发生机制提供理论依据，并为糖尿病心肌病的防治提供有效的分子靶点，也为NHE1抑制剂对糖尿病心肌损伤保护作用的临床应用提供实验基础。
Application Abstract: Diabetic cardiomyopathy(DCM)is a disease of cardiac structure and function disorder caused by diabetes mellitus.The cardiac injury caused by intracellular calcium overload is one of the important factors.In this study,DCM model was established by high fat diet combined with low-doseintraperitoneal injection of STZ,and H9c2 cardiomyocyte injury model was induced by high glucose in vitro.The role of ASICs and PICK1 in the pathogenesis of DCM was studied by small animal ultrasound imaging,immunohistochemistry,patch clamp,calcium ion imaging and molecular biology technologys.Results are shown as followed:①The content of PICK1 protein in myocardial tissue of diabetic rats increased gradually with the progression of the disease.Inhibition of ASIC1a could improve the cardiac function,reduce the contents of serum creatine kinase and lactate dehydrogenase,alleviate myocardial injury and cell apoptosis.In high glucose environment,pctx1 dose dependently alleviated the cell injury induced by high glucose;②Inhibition of NAH exchanger 1 can improve cardiac injury in diabetic db/db mice.The mechanism may be related to the improvement of high glucose,high fat and insulin resistance,antioxidant stress and regulation of calpain and Akt/GSK-3 β protein;③Different concentrations of high-fat(PA)can lead to apoptosis of H9c2 cardiomyocytes,which may be related to the increased production of reactive oxygen species.Loripram can protect H9c2 cardiomyocytes from lipid toxicity induced by PA,and its protective mechanism may be related to the inhibition of intracellular oxidative stress and apoptosis;④Mettl3 dependent m6rna methylation may affect the homeostasis of redox and mediate DOX cardiotoxicity.This study will provide theoretical basis for exploring the mechanism of diabetic cardiomyopathy with ASICs and PICK1 as targets,and provide effective molecular targets for the prevention and treatment of diabetic cardiomyopathy,and also provide experimental basis for clinical application of NHE1 inhibitors on diabetic myocardial injury.
项目受资助省
湖北省
