Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice
Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice
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DOI：
10.1194/jlr.c600025-jlr200
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发表时间：
2007-04-01
影响因子：
6.5
通讯作者：
Crooke, Rosanne M.
中科院分区：
文献类型：
--
作者：
Graham, Mark J.;Lemonidis, Kristina M.;Crooke, Rosanne M.
蛋白转化酶subtilisin/ keexin type 9 （PCSK9）是一个蛋白酶家族的成员，被认为通过一种尚未明确的机制促进低密度脂蛋白受体（LDLR）的降解。我们开发了第二代针对小鼠PCSK9的反义寡核苷酸（ASO）抑制剂，以确定它们作为降脂剂的潜力。给高脂喂养的小鼠注射PCSK9 ASO 6周后，总胆固醇和LDL分别降低53%和38%。此外，抑制PCSK9的表达导致肝脏LDLR蛋白水平增加2倍。这种表型与先前在pcsk9缺陷小鼠中报道的非常相似。在低密度脂蛋白缺陷小鼠中没有降低胆固醇的作用，有效地证明了该受体在介导PCSK9抑制的降脂作用中的关键作用。PCSK9的反义抑制是治疗人类高胆固醇血症的一种有吸引力的新方法。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of a family of proteases that is thought to promote the degradation of the low density lipoprotein receptor (LDLR) through an as yet undefined mechanism. We developed second generation antisense oligonucleotide (ASO) inhibitors targeting murine PCSK9 to determine their potential as lipid-lowering agents. Administration of a PCSK9 ASO to high fat-fed mice for 6 weeks reduced total cholesterol and LDL by 53% and 38%, respectively. Moreover, inhibition of PCSK9 expression resulted in a 2-fold increase in hepatic LDLR protein levels. This phenotype closely resembles that reported previously in Pcsk9-deficient mice. The absence of cholesterol lowering in Ldlr-deficient mice effectively demonstrated a critical role for this receptor in mediating the lipid-lowering effects of PCSK9 inhibition. Antisense inhibition of PCSK9 is an attractive and novel therapeutic approach for treating hypercholesterolemia in human.