Abstract Body: Introduction Biological sex determines post-MI cardiac outcomes, yet contributions of estrogen versus sex chromosomes remain unresolved. Post-MI repair depends on macrophage M1→M2 transition; failure drives adverse remodeling. Dissecting hormonal from chromosomal mechanisms is essential for identifying sex-specific targets.
Hypothesis Estrogen and sex chromosome complement constitute two independent cardioprotective axes. Estrogen loss (OVX) impairs inflammatory resolution while preserving structure; the Y chromosome imposes an estrogen-independent epigenetic barrier to M2 polarization.
Aims Using female (F), OVX, and male (M) C57BL/6 mice post-LAD ligation, we: (1) characterized sex- and estrogen-dependent differences in cardiac function and morphometry; (2) identified transcriptomic programs diverging despite equivalent functional outcomes; and (3) determined whether divergence reflects hormonal, chromosomal, or combined mechanisms.
Methods F (n=10/8/5/7), OVX (n=10/8/5/7), and M (n=10/10/7/7) mice underwent sham or LAD ligation. EF and FS were assessed at d3–5, d7, and d14. HW/TL and HW/BW were quantified (n=5/3/7 per group). Bulk cardiac RNA-seq (n=5/group, d14) and H3 ELISA (21 marks) in polarized BMDMs were performed. One-way ANOVA; p<0.05.
Results Males showed significantly reduced EF/FS and elevated HW/TL vs both F and OVX at all timepoints (p<0.031 to p<0.0002); F and OVX were equivalent across all measures. Despite this, F vs OVX yielded 40 DEGs at d14 — females upregulated a metabolic program while OVX retained active M1 markers. F vs M yielded 64 DEGs, with Y-linked epigenetic regulators and the full M1 program elevated in males. OVX vs M yielded only 12 DEGs, all sex chromosome-encoded, with zero inflammatory genes differing. No genome-wide histone differences were detected in male vs female BMDMs (all p>0.13), consistent with a locus-specific mechanism.
Conclusions Estrogen suppresses M1 persistence and activates cardioprotective programs; its loss produces transcriptomic vulnerability despite preserved d14 structure. Y-linked chromatin regulators impose a locus-specific epigenetic barrier to M2 polarization independent of estrogen. Full protection requires both axes. Y-linked chromatin regulators represent candidate therapeutic targets for sex-dimorphic post-MI outcomes.