Abstract Body (Do not enter title and authors here): Background: Left ventricular (LV) remodeling after myocardial infarction (MI) leads to heart failure, a leading cause of death. We recently demonstrated that dietary 7KC exacerbates myocardial ischemia-reperfusion injury through macrophage-mediated inflammation, in which endoplasmic reticulum (ER) stress mediated by the activation of ER oxidoreductase 1 (ERO1) triggers oxidative stress.
Hypothesis: Dietary oxysterols may exacerbate post-MI remodeling via ERO-1-mediated macrophage activation.
Methods: We induced myocardial infarction in C57BL6/J mice fed a high-fat high-cholesterol diet (HFHCD) or a HFHCD containing 0.1% 7KC (7KC-HFHCD) by LAD ligation. Cardiac function was assessed using echocardiography. Cardiac hypertrophy, fibrosis and inflammation were assessed by histopathological analysis. Gene expression of CD45⁺ cells was explored by scRNA-seq analysis. We developed a novel macrophage-targeted siERO1 encapsulated lipid nanoparticle (siERO1-NP).
Results: Three weeks after myocardial infarction, 7KC-HFHCD increased post-infarction LV end-diastolic volume (165 ± 36 mm³ vs. 121 ± 24 mm³, P = 0.006) and decreased the LV ejection fraction (13.2 ± 5.5% vs. 21.3 ± 7.2%, P = 0.036) compared to HFHCD. Myocardial thinning in the infarct zone, fibrosis in the peri-infarct zone and cardiomyocyte hypertrophy in the non-infarcted zone were exacerbated in the 7KC-HFHCD group compared to the HFHCD. These results were consistent with increased Ly-6C^high monocyte and macrophage accumulation, along with elevated MMP activity and reduced collagen content in the post-MI myocardium. Machine learning-based cell type annotation of CD45⁺cells in the post-MI myocardium revealed that S100A9⁺ inflammatory monocytes (CL1) and Ly6C2⁺CCR2⁺ inflammatory macrophages (CL3) increased, while Arg1⁺CCR2⁺ anti-inflammatory macrophages (CL2) decreased and Lyve1⁺resident macrophages (CL4) disappeared in the 7KC-HFHCD group compared to the HFHCD group (Fig. A). The KEGG pathway analysis of the DEGs between the two groups identified “protein processing in ER” as the fourth most enriched pathway. siERO1-NP administered on days 0 and 1 post-coronary ligation (0.5 mg/kg/day, i.v.) improved 7KC-induced exacerbation of the post-MI LV remodeling (Fig. B, n = 6-15).
Conclusions: Dietary 7KC may exacerbate post-MI LV remodeling through macrophage activation mediated by ERO1. Macrophage ER stress may be a promising therapeutic target for post-MI LV remodeling exacerbated by dietary oxysterols.