Key result
PCSK9 inhibition significantly reduces AAA diameter in mouse models, while upregulation increases it.
Why the study?
Abdominal aortic aneurysm rupture causes substantial mortality without effective drug therapies, while PCSK9 influences processes implicated in AAA pathogenesis.
Does PCSK9 upregulation or inhibition affect AAA diameter in mouse models of abdominal aortic aneurysm?
Meta-Analysis (n=185)
Does PCSK9 upregulation or inhibition affect AAA diameter in mouse models of abdominal aortic aneurysm?
PCSK9 inhibition reduces abdominal aortic aneurysm diameter in mouse models, highlighting a potential therapeutic target for limiting AAA growth.
PCSK9 upregulation enlarges AAA in mice; extends experimental data but leaves human therapeutic implications open.
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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Wesley et al. (2026) conducted a meta-analysis in Abdominal aortic aneurysm (n=185). PCSK9 inhibition vs. Control was evaluated on AAA diameter (SMD -0.97, 95% CI -1.44 to -0.49, p=<0.0001). In mouse models, PCSK9 inhibition significantly reduced abdominal aortic aneurysm diameter (SMD -0.97; 95% CI -1.44 to -0.49; P<0.0001), while PCSK9 upregulation increased it.
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