Hypercholesterolemia induced by a PCSK9 gain-of-function mutation augments angiotensin II-induced abdominal aortic aneurysms in C57BL/6 mice-brief report

Hong Lu, Deborah A. Howatt, Anju Balakrishnan, Mark J. Graham, Adam E. Mullick, Alan Daugherty

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Objective-Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-Associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)-induced abdominal aortic aneurysms. Approach and Results-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 3 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 agematched male low-density lipoprotein receptor-/- mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor-/- mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor-/- mice did not influence AngII-induced abdominal aortic aneurysms. Conclusion-AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with AngII.

Original languageEnglish
Pages (from-to)1753-1757
Number of pages5
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number9
StatePublished - Sep 1 2016

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health under award number R01 HL133723 to A. Daugherty. The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2016 American Heart Association, Inc.


  • Aortic aneurysms
  • Atherosclerosis
  • Hypercholesterolemia
  • Low-density lipoprotein
  • Mouse
  • Pcsk9 protein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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