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. 2025 Sep 29.
doi: 10.1111/dom.70154. Online ahead of print.

Shared and divergent acute cardiovascular risk protein responses to lipid infusion in women with and without PCOS

Ebrahim Rajab  1 , Abu Saleh Md Moin  2 , Manjula Nandakumar  2 , Thozhukat Sathyapalan  3 , Alexandra E Butler  2 , Stephen L Atkin  2
Affiliations

Shared and divergent acute cardiovascular risk protein responses to lipid infusion in women with and without PCOS

Ebrahim Rajab et al. Diabetes Obes Metab. .

Abstract

Aims: Elevated circulating lipids are linked to cardiovascular disease (CVD), especially in insulin-resistant states like polycystic ovary syndrome (PCOS), but their effects on cardiovascular risk proteins (CVRPs) remain unclear. This study used a two-step approach to examine acute cardiovascular proteomic responses to lipid-induced metabolic stress. We first identified proteins altered by lipids and insulin in healthy control (HC) women, then assessed whether these responses were similar or divergent in women with PCOS.

Methods: In a randomised cross-over study, 10 healthy controls and 12 women with PCOS underwent 5-h saline (control) or intralipid infusions. After 3 h, a 2-h hyperinsulinemic-euglycemic clamp was initiated. Plasma CVRP expression was assessed at baseline, post-lipid (180 min) and post-clamp (300 min) using SOMAscan proteomics. STRING and pathway enrichment analyses were performed to explore functional associations.

Results: In the HC group, lipid infusion altered the expression of 11 out of 54 CVRPs including increases in RANK, IL2RA, TACI, SLAF5 and DCN (p <0.05) and decreases in THPO, BOC, SOD2, FGF23, and AgRP (p <0.05). Most changes reversed with insulin, but BOC, SOD2, MMP12, FGF23, and DCN remained dysregulated. In PCOS, responses mirrored the HC group except for lower AgRP following lipid infusion (p <0.01), and persistent elevation of SLAF5 and DCN following insulin (p <0.05). Enrichment analysis linked altered proteins to immune activation, cell proliferation, and cytokine-receptor signalling.

Conclusion: Acute lipid infusion revealed shared and phenotype-specific proteomic responses linked to early vascular stress. In PCOS, persistent dysregulation suggests reduced metabolic adaptability, with exploratory signals that may complement established biomarkers of early cardiovascular risk.

Keywords: cardiovascular biomarkers; insulin resistance; non‐esterified fatty acids; premenopausal; vascular remodelling, proteomics.

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