Key result
Macrophage-specific NCOR1 deletion prevents HFpEF progression by suppressing NLRP3-IL1b-mediated inflammation in preclinical models.
Why the study?
The inflammatory response is a key player in HFpEF and macrophage activation may lead to pathological cardiac remodeling, but the underlying mechanisms underpinning macrophage inflammation in HFpEF are poorly understood.
Does myeloid-specific deletion or depletion of Nuclear Receptor Co-repressor 1 (NCOR1) prevent macrophage-driven inflammation and diastolic dysfunction in experimental models of heart failure with preserved ejection fraction (HFpEF)?
Does myeloid-specific deletion or depletion of Nuclear Receptor Co-repressor 1 (NCOR1) prevent macrophage-driven inflammation and diastolic dysfunction in experimental models of heart failure with preserved ejection fraction (HFpEF)?
This translational study identifies macrophage NCOR1 as a key molecular checkpoint driving inflammation via the NLRP3-IL1b pathway in HFpEF, demonstrating that its deletion prevents diastolic dysfunction, lung congestion, and exercise intolerance in a murine model.
Macrophage MHC-II upregulation and IFNγ response in HFpEF myocardium may fuel inflammation; leaves open whether targeting this axis modifies progression.
Background Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood. Recent studies have shown that macrophages are active players in the myocardium and their activation may lead to pathological cardiac remodeling. Purpose to investigate the mechanisms underpinning macrophage inflammation in HFpEF. Methods FACS analysis, transcriptional profiling of immune cell populations by single nuclei RNA-seq (snRNAseq) in human and murine HFpEF hearts as well as in vitro experiments were employed. RAW-264.7 cells exposed to metabolic stress (palmitic acid, PA) and bone marrow-derived macrophages from healthy and HFpEF mice were used. The effects of macrophage secretome on cultured primary cardiomyocytes and endothelial cells were also investigated. Induction of HFpEF in mice was achieved through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) while Treadmill test was used to investigate exercise tolerance. Data obtained in mice were validated in left ventricular (LV) specimens from control donors and HFpEF patients. Based on scRNA-seq data showing Nuclear Receptor Co-repressor 1 (Ncor1) as a top-ranking gene in HFpEF macrophages, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo role of NCOR1 in HFpEF. Results snRNA-seq of human failing hearts showed an expansion of the macrophage population together with a marked upregulation of NCOR1 in the macrophage cluster. Experiments in LV specimens from HFpEF patients showed an increase in pro-inflammatory macrophage markers (M1) as compared to age-matched control donors. snRNA-seq of HFpEF vs control mouse hearts confirmed the expansion of the M1 macrophage population, the upregulation of inflammatory molecules (ICAM1, ICAM2, E-selectin) and fibrosis-related genes. Of interest, macrophage NCOR1 deletion in HFpEF mice prevented diastolic dysfunction - assessed by E/e’ ratio and isovolumic relaxation time (IVRT) - lung congestion and exercise intolerance. These findings were associated with reduced myocardial inflammation in Ncor1-KO mice as proved by sn-RNAseq. In vitro assays showed that metabolic stress by PA recapitulated NCOR1 upregulation and subsequent activation of the NLRP3-IL1b pathway; whereas NCOR1 depletion prevented macrophage inflammation. Finally, NCOR1 depletion in PA-treated macrophages prevented secretome alterations and preserved the function and viability of cardiomyocytes and endothelial cells, thus suggesting an active role of macrophage NCOR1 within the cardiac micro-environment. Conclusion Our findings shed light on a new molecular checkpoint of macrophage activation and set the stage for mechanism-based therapeutic strategies to prevent inflammation and cardiac dysfunction in HFpEF.
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Gorica et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Myeloid cell-specific NCOR1 knockout (Ncor1-KO) / NCOR1 depletion vs. Control / wild-type HFpEF mice and age-matched human control donors was evaluated on Diastolic dysfunction (E/e' ratio and IVRT), lung congestion, exercise intolerance, and macrophage-driven myocardial inflammation via the NLRP3-IL1b pathway. Macrophage-specific NCOR1 deletion in HFpEF mice prevented diastolic dysfunction (E/e' ratio, IVRT), lung congestion, and exercise intolerance by reducing NLRP3-IL1b-mediated inflammation.
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