LRP3 (low-density lipoprotein receptor-related protein 3), potential metabolic-inflammatory dual regulatory targets of atherosclerosis

Abstract Background Atherosclerosis (AS), the primary pathological driver of cardiovascular diseases, presents persistent therapeutic challenges, underscoring the need for novel therapeutic targets. LRP3, a member of the LDL receptor family, modulates lipid metabolism and inflammatory responses. Studies in rat chondrocytes demonstrate its downregulation under high cholesterol or TNF-α stimulation. While current AS research predominantly targets canonical pathways (e.g., LDLR, ABCA1), LRP3's role in AS remains uncharacterized. Systematic exploration of its potential as a "metabolism-inflammation crosstalk node" could address the knowledge gap regarding non-canonical lipoprotein receptors in vascular pathology. Purpose This project aims to investigate the mechanisms of LRP3 in atherosclerosis, elucidating its novel function in inflammatory cascades beyond lipid dysregulation. Methods A single dose of AAV8-Pcsk9D377Y (3×1011vg per mouse) was injected into the tail vein of mice. Atherosclerosis was induced by feeding a high-cholesterol diet (HCD; 20% fat, 1.25% cholesterol). Human arterial transcriptomes were analyzed using publicly available datasets (GEO accession: GSE100927). Body composition and blood lipid levels were measured by low field nuclear magnetic resonance analyzer and biochemical analyzer respectively. UHPLC-MS/MS analyses were used to take cholesterol components.The aortic roots were subjected to masson tricolor staining and 0.3% oil red O staining. All data were presented as means ± SEM. For comparison between 2 groups, the unpaired t test was employed. A P value less than 0.05 was deemed statistically substantial. Results To investigate LRP3's role in atherosclerosis, we observed reduced LRP3 expression in atherosclerotic plaques compared to healthy arteries (Fig. 1A). Untreated LRP3-/-mice exhibited significantly lower HDL-C (high density lipoprotein cholesterol) levels than WT (Fig. 1B), suggesting LRP3 intrinsically modulates cholesterol distribution.Post-diet induction (Fig. 1C), LRP3-/- mice exhibited elevated fat mass with reduced lean mass and free water compared to WT (Fig. 1D). LRP3-/-mice also showed elevated plasma LDL-C (low density lipoprotein cholesterol) and triglycerides, reduced HDL-C (Fig. 1E). Notably, LRP3-/- mice displayed reduced leukocyte counts, implying its regulatory role in immune responses (Fig. 1F). Histological analysis demonstrated increased fibrosis and plaque area in the aortic sinus of LRP3-/- mice (Fig. 1G). Collectively, LRP3 deficiency aggravates atherosclerosis through dysregulated lipid metabolism and immune modulation. Conclusion Our study demonstrates that LRP3-deficient mice exhibit reduced HDL-C and impaired immune responses. Notably, HCD further accelerated atherosclerosis progression in these mice. These findings suggest LRP3 concurrently regulates lipid metabolism and immune-inflammatory pathways, positioning it as a promising dual-target therapeutic candidate.LRP3 deficiency aggravates AS