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

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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