Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report.
Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II-Induced Abdominal Aortic Aneurysms in C57BL/6 Mice-Brief Report.
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DOI：
10.1161/atvbaha.116.307613
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Daugherty A
中科院分区：
文献类型：
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作者：
Lu H;Howatt DA;Balakrishnan A;Graham MJ;Mullick AE;Daugherty A
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）的功能获得性突变导致高胆固醇血症。本研究旨在确定用表达小鼠PCSK 9功能获得性突变的腺相关病毒载体（AAV）感染胆固醇正常小鼠是否会增加血管紧张素II（AngII）诱导的腹主动脉瘤（AAA）。在最初的研究中，雄性C57 BL/6小鼠腹腔内注射三剂空载体或PCSK 9功能获得性突变（D377 Y）.AAV，并喂食富含饱和脂肪的饮食6周。在AAV注射后两周，向小鼠输注AngII持续4周。在注射含有PCSK 9D 377 Y突变的AAV的小鼠中，血浆PCSK 9浓度呈剂量依赖性增加，并且与血浆胆固醇浓度升高呈正相关。用中等和高剂量的PCSK9D377Y.AAV感染导致输注AngII的C57 BL/6小鼠的腹部血管最大宽度的等效增加。因此，在后续实验中使用了中间剂量。然后，我们确定了PCSK9D377Y.AAV感染对5种血脂正常小鼠品系的影响，证明C57 BL/6小鼠对这种AAV感染最易感。还将PCSK9D377Y.AAV感染的雄性C57 BL/6小鼠与年龄匹配的雄性低密度脂蛋白（LDL）受体−/−小鼠进行了比较。尽管感染PCSK9D377Y.AAV的小鼠血浆胆固醇浓度较低，但与LDL受体−/−小鼠相比，这些小鼠的AAA形成相当。在另一项研究中，雄性LDL受体−/−小鼠中PCSK 9反义寡核苷酸降低血浆PCSK 9浓度并不影响AngII诱导的AAA。AAV介导的小鼠PCSK 9功能获得性突变感染是一种快速、简便、有效的方法，可在输注AngII的C57 BL/6小鼠中诱导高胆固醇血症并促进AAA。
Gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 (PCSK9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral vector (AAV) expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs). In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y).AAV at three doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose-dependently in mice injected with AAV containing PCSK9D377Y mutation, and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein (LDL) receptor −/− mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent AAA formation, compared to LDL receptor −/− mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male LDL receptor −/− mice did not influence AngII-induced AAAs. AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting AAAs in C57BL/6 mice infused with AngII.