DOI: 10.1161/atvbaha.126.324982 ISSN: 1079-5642

Systematic Review and Meta-Analysis Examining the Effect of Upregulation and Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 in Mouse Models of Abdominal Aortic Aneurysm

Callan D. Wesley, Shivshankar Thanigaimani, Abid Khan, Jonathan Golledge
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BACKGROUND:

Abdominal aortic aneurysm (AAA) rupture is an important cause of death worldwide, with no effective drug therapies currently available. PCSK9 (proprotein convertase subtilisin/kexin type 9) regulates LDL-C (low-density lipoprotein-cholesterol) and modulates vascular inflammation, smooth muscle cell apoptosis, and extracellular matrix remodeling, all implicated in AAA pathogenesis.

METHODS:

We conducted a systematic review and meta-analysis of studies evaluating the effects of PCSK9 upregulation or inhibition on AAA in mouse models. The primary outcome was AAA diameter, with secondary outcomes including lipid and inflammatory markers. Five articles (11 studies, 101 experimental, and 84 control mice) were included. Meta-analysis results were reported as standardized mean difference and 95% CIs. A custom tool, which integrated Cochrane criteria, ARRIVE guidelines, and methods from prior systematic reviews, was used to assess the risk of bias.

RESULTS:

PCSK9 upregulation significantly increased AAA diameter (standardized mean difference, 1.07 [95% CI, 0.33–1.81]; P =0.005) and blood concentrations of total cholesterol, LDL (low-density lipoprotein), and triglycerides while significantly reducing blood concentrations of high-density lipoprotein. PCSK9 upregulation also increased aortic IL (interleukin)-6 and IL1-β concentrations, as assessed by aortic immunohistochemical staining. PCSK9 inhibition significantly reduced AAA diameter (standardized mean difference, −0.97 [95% CI, −1.44 to −0.49]; P <0.0001) and blood concentrations of IL-1β, IL-6, and TNF-α (tumor necrosis factor-alpha). Risk of bias was low-to-moderate across studies.

CONCLUSIONS:

In mouse models, PCSK9 upregulation promoted larger AAAs, while PCSK9 inhibition promoted smaller AAAs. These effects were associated with changes in lipid and inflammatory markers. PCSK9 inhibition may be a target to limit AAA growth.

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