A-143 Sex-Dependent Cardiac Driven Metabolic Remodeling Identified by Integrated Multi-Omics in Mouse and Human Coronary Artery Disease

Abstract

Cardiometabolic diseases, including coronary artery disease (CAD) and metabolic syndrome, are associated with systemic metabolic and inflammatory dysregulation and co-occur with type 2 diabetes (T2D). However, regulation of extra-cardiac tissues and heart-derived circulating signals (cardiokines) remain poorly defined, particularly in females. Consequently, sex-dependent cardiokines and metabolic pathways relevant to disease progression and biomarker discovery remain insufficiently understood. In a cardiac-specific transgenic mouse model of cardiometabolic disease (Tg) under high- fat diet (HFD) stress, females develop maladaptive cardiac remodeling, versus cardioprotection in males, accompanied by sex-dependent systemic metabolic adaptation. Tg females display impaired thermogenic activation in brown adipose tissue (BAT) despite preserved tissue morphology, while males demonstrate enhanced metabolic flexibility. Since genetic manipulation is restricted to cardiomyocytes, the fat serves as a peripheral readout of cardiac driven signaling. Longitudinal sex- and genotype-dependent shifts in circulating metabolites were enriched for inflammatory and metabolic pathways, supporting systemic metabolic reprogramming. High-performance liquid chromatography- mass spectrometry (HPLC-MS) multi-omics profiling was performed in male and female Tg and non-transgenic littermate control (NLC) mice under HFD stress and in human serum from CAD +/- T2D patients. Semi-targeted lipidomics assessed inflammatory lipid mediators and polyunsaturated fatty acid (PUFA) precursors in mouse serum (16 weeks) and heart and BAT (4 and 16 weeks). Lipid indices were calculated to capture pathway-level shifts. Untargeted mouse and human serum proteomics were also performed and subjected to gene ontology and enrichment analysis (ShinyGo). Results were integrated with a prior targeted metabolomic panel, and statistical readouts assessed main and interaction effects. Upregulated proteins in female Tg mice at baseline were derived from short, rapidly translatable coding genes enriched in central metabolic pathways, consistent with coordinated stress-responsive secretion rather than random protein release. In human serum, sex differences emerged independent of T2D. Females showed reduced abundance of proteins involved in immune regulation, extracellular matrix remodeling, protease balance, and glycolytic metabolism, including a-enolase (ENO1) (M/F fold change = 7.5, p = 0.0422), a significant regulator of cellular energy flux. Cross-species pathway overlap supported conserved, sex-biased metabolic reprogramming. Targeted lipidomics revealed tissue- and sex-specific remodeling of inflammatory lipid mediators and their PUFA precursors. Notably, cardiac 12-HETE was suppressed early in Tg males versus NLCs (351.6 vs 955.6 ng/g; p= 0.0112) and increased later in Tg females (849.7 vs 301.9 ng/g; p= 0.0461). Similarly, upstream PUFA precursors showed sex- and genotype-dependent shifts in heart and BAT under chronic cardiac stress. For example, increased cardiac linoleic acid breakdown (12,13-DiHOME/linoleic acid index) into oxylipins resolves by 4 weeks in Tg males, but 16 weeks in Tg females, while unchanged in BAT and serum. Cardiac stress drives coordinated, sex-dependent remodeling of circulating proteins and cardiac LA-derived lipid mediator balance. Temporal divergence between males and females suggests adaptive versus maladaptive metabolic trajectories with potential downstream effects on peripheral fuel utilization and thermogenic regulation. Cross-species convergence supports integrated proteomic and lipid indices as sex-informed biomarkers for disease stratification, translation assay development, and therapeutic targeting in obesity and cardiometabolic disease.