【作者】 张治宇；

【导师】 殷仁富； 陈金明； 王爱华；

【作者基本信息】 第二军医大学 ， 内科学， 2007， 博士

【摘要】 糖尿病患者血浆脂质升高的同时，心肌内亦存在脂质蓄积，并伴有心肌细胞凋亡。体外培养也发现饱和脂肪酸可诱导多种细胞出现凋亡。为探讨饱和脂肪酸损伤心肌的机制，本文第一部分使用高脂喂养结合腹腔注射小计量链脲菌素构建2型糖尿病大鼠，观察大鼠脂质代谢紊乱、心肌细胞凋亡、心功能的变化情况，并使用代谢药物左旋卡尼汀进行干预，结果发现，糖尿病大鼠在血浆脂质升高的同时伴有心肌细胞膜上FAT／CD36蛋白含量增加、心肌脂质蓄积、心肌细胞凋亡、心功能受损；L-CN具有显著保护作用。为进一步研究饱和脂肪酸对心肌的损伤作用，本文第二部分使用palmitate处理乳鼠心肌细胞，结果发现palmitate可显著升高细胞凋亡率，CPT-1抑制剂perhexiline可加重palmitate诱导的心肌细胞凋亡，CPT-1辅助因子L-CN可减轻palmitate诱导的心肌细胞凋亡。既往研究发现饱和脂肪酸可诱导胰岛β细胞发生内质网应激，因此本文第三部分初步探讨了内质网应激在palmitate诱导心肌细胞凋亡中的作用，结果发现palmitate可激活心肌细胞多条参与内质网应激的信号通路。更多还原

【Abstract】 Recently, Lipid accumulation in the heart has been observed under conditions of elevatedplasma free fatty acids, such as Type 2 diabetes mellitus and is linked with cardiomyocyte apoptosis. It isalso found that apoptosis can be induced by saturated fatty acid in cultured cell. In order to study themechanism of myocardial injury by saturated fatty acid, in first part of this study we got type 2 diabetic ratsby HFD-fed and STZ-treated, and observed metabolic disorder, cardiomyocyte apoptosis and heart functionof diabetic rats. At the same time diabetic rats were treated by metabolic drug L-CN. We found that plasmalipid level was increased followed by augment of FAT/CD36 on cardiomyocyte membrane, cardiomyocyteapoptosis, degresion of heart function, and L-CN showed significantly protective effect. For furtherstudying saturated fatty acid induced injury, we cultured neonatal rat cardiomyocytes with palmitate ofdifferent concentration. Significant effect of palmitate induced cardiomyocyte apoptosis was found, whitchcould be aggravated by CPT-1 inhibitor perhexiline and be lessened by CPT-1 cofactor L-CN. Previousstudies show ER stress occurs in palmitate-treated pancreaticβcell, therefore the effect of ER stress inpalmitate-induced cardiomyocyte apoptosis was approached in part 3 of this study. The results indicatedthat ER stress contributed to palmitate-induced cardiomyocyte apoptosis.更多还原