Key result
PPARalpha overexpression reduces atherosclerosis and hypercholesterolemia driven by gain-of-function PCSK9 in mice.
Why the study?
Does PCSK9 with a gain of function D374Y mutation aggravate atherosclerosis by inhibiting PPARα expression in mouse models?
Does PCSK9 with a gain of function D374Y mutation aggravate atherosclerosis by inhibiting PPARα expression in mouse models?
Answers are grounded in this paper and cite their sources.
PCSK9 with a gain-of-function mutation promotes atherosclerosis progression by increasing plasma lipids and inflammation, an effect that can be mitigated by PPARα overexpression.
The preprotein convertase, Bacillus subtilis protease/kexin type 9 serine protease (PCSK9), has garnered significant attention as a potential lipid lowering and therapeutic drug target for atherosclerosis (AS). Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in various tissues and has crucial roles in lipid metabolism and the inflammatory response; however, the precise impact of PCSK9 on AS progression through its regulation of PPARα remains uncertain. The present study aimed to examine the impact of introducing stable liver transduction of human derived PCSK9 with a gain of function D374Y mutation (PCSK9DY) into systemic PPARα knockout mice (PPARα-/-) on plasma lipid levels and AS. Enzymatic assays were employed to evaluate plasma lipid concentrations at various time points, and aortic plaque formation and the degree of inflammatory infiltration quantified. Subsequently, we validated our in vivo results using mouse primary peritoneal macrophages (MPMs). Furthermore, AAV8.2-PPARα virus vector was transduced into transgenic mice of human PCSK9(hPCSK9DY-Tg) by tail vein, and the changes of plasma lipid level and AS were detected. PCSK9DY expression exacerbated symptoms of hypercholesterolemia in PPARα-/- mice. En face analysis and quantification of aortic root sections demonstrated a significant increase in aortic plaque area and inflammatory infiltration in PCSK9DY transduced PPARα-/- mice. Secretion of inflammatory cytokines was elevated in PCSK9DY transduced PPARα-/- mice. In vitro, recombinant hPCSK9 protein promotes the foam cell formation and inflammatory cytokines secretion of PPARα-/- MPMs by increasing the expression of SR-A and TLR4/NF-κB pathway proteins. AAV8.2-PPARα virus vector can reduce the plasma lipid level and AS formation in hPCSK9DY-Tg mice. These finding demonstrate that PCSK9DY expression notably facilitated AS progression in PPARα-/- mice by increasing plasma lipid concentrations and inflammation. However, overexpression of PPARα can reduce AS formation in hPCSK9DY-Tg mice.
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Cui et al. (2025) studied Atherosclerosis. PCSK9 with a gain of function D374Y mutation (PCSK9DY) and AAV8.2-PPARα virus vector was evaluated on Plasma lipid levels, aortic plaque formation, and inflammatory infiltration. PCSK9DY expression exacerbated hypercholesterolemia and atherosclerosis in PPARα-/- mice, while overexpression of PPARα reduced atherosclerosis formation in hPCSK9DY-Tg mice.
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