Elucidation of endothelial lipase as a new therapeutic strategy foratherosclerosis: a study using transgenic rabbits

现有证据表明，内皮脂肪酶(EL)在高密度脂蛋白(HDL)代谢中起重要作用。首先，我们克隆了兔REL基因和Rel基因。通过Northern印迹、实时RT-PCR、Western印迹和原位杂交，我们发现Rel基因在肝脏、睾丸和肾上腺等与胆固醇合成相关的器官中高表达，在肺、肾、骨髓和小肠中也有表达。WHHL兔血浆高密度脂蛋白水平与血浆Rel蛋白水平及肝组织Rel基因表达水平呈负相关。在兔体内注射REL特异性反义寡核苷酸可引起血浆大小HDL的升高。此外，我们还证实在WHHL兔的动脉粥样硬化病变中，Rel mRNA在内皮细胞和巨噬细胞中都有表达。REL在多种组织中表达，可能具有多种生理和病理生理功能，如调节胆固醇代谢和动脉粥样硬化等。结果提示，EL是兔血浆高密度脂蛋白水平的重要调节因子。此外，我们还培育了两只转基因兔，在肝脏中表达不同水平的人EL

Existing evidence suggests that endothelial lipase (EL) plays an important role inhigh-density-lipoprotein (HDL) metabolism. First, we cloned the rEL cDNA and gene ofrabbits. Using Northern blotting, real-time RT-PCR, Western blotting, and in situhybridization, we revealed that rEL mRNA was highly expressed in the cholesterolsynthesis-related organs including the liver, testis, and adrenal along with itsexpression in the lung, kidney, bone marrow, and small intestine. The plasma HDL levelsin WHHL rabbits were inversely associated with high levels of plasma rEL proteins andhepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides intorabbits resulted in an elevation of plasma large-sized HDLs. Furthermore, we demonstratedthat the rEL mRNA was expressed by both endothelial cells and macrophages in the lesionsof aortic atherosclerosis of WHHL rabbits. rEL is expressed in multiple tissues and mayhave many physiological and pathophysiological functions such as in the regulation ofcholesterol metabolism and atherosclerosis. Our results suggest that EL is an importantregulator of plasma HDL levels in rabbits. In addition, we generated two transgenicrabbits expressing different levels of human EL in the liver