Myeloid cells orchestrate vascular inflammation through transcriptional programs that control their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, our understanding of the transcriptional regulation of myeloid cell behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation and is essential for maintaining stem and progenitor cell fitness. Here, we investigate NF-Y activity in myeloid cell function and survival using integrated single-cell transcriptomics and myeloid-specific deletion of the NF-YA subunit. At RNA level, NF-Y subunit transcripts were detected across myeloid compartments, with NF-YA enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low NF-YA levels were associated with macrophages exhibiting lipid-handling and phagocytic signatures and with neutrophils displaying a proinflammatory phenotype. NF-Y deficiency impaired neutrophil adhesion and rolling, increased their susceptibility to apoptosis, and promoted activation and lipid accumulation in macrophages. In vivo, myeloid NF-YA deficiency reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, leading to larger and more unstable atherosclerotic lesions, and aggravated both atherosclerosis and injury-induced neointimal thickening. These findings identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.
Carlos Silvestre-Roig, J. González-Granado, C. Osei-Sarpong et al.· Journal of Leukocyte Biology· 0 citations
BACKGROUND
Plasma levels of haptoglobin and IgA2 (immunoglobulin A2) have recently been associated with subclinical atherosclerosis in European cohorts. We sought to validate these findings in an American population and to determine whether these biomarkers predict all-cause mortality or major cardiovascular adverse events beyond traditional risk scales (Framingham Risk Score) or vascular imaging.
METHODS
We analyzed 5328 asymptomatic US adults (mean age 69 years, 56.9% women) from the BioImage study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population; NCT00738725). Subjects underwent carotid plaque burden assessment by ultrasound, coronary artery calcium by computed tomography, and baseline plasma haptoglobin and IgA2 levels measurement by immunoturbidimetry. The end point was a composite of major cardiovascular adverse events and all-cause death during follow-up.
RESULTS
Haptoglobin and IgA2 correlated significantly with carotid plaque burden and coronary artery calcium, independent of Framingham Risk Score. After a median follow-up of 4.6 years, 466 participants (8.8%) experienced the composite outcome. Haptoglobin and IgA2 independently predicted the outcome, and associations remained significant after further adjustment for carotid plaque burden or coronary artery calcium. Similar results were observed for predictive capacity of high-sensitivity C-reactive protein. Individuals with high levels of all biomarkers (above the median) had a 2-fold higher event rate compared with those with low levels. Combined biomarker assessment, albeit modestly, significantly improved risk prediction beyond Framingham Risk Score and imaging.
CONCLUSIONS
Haptoglobin and IgA2 predict the composite outcome of major cardiovascular adverse events and all-cause death, independently to Framingham Risk Score, in asymptomatic American adults. Their measurement, alone or in combination with imaging, may enhance cardiovascular risk stratification in primary prevention.
A. García-Álvarez, V. Fuster, Estefanía Núñez et al.· Journal of the American Hear...· 0 citations
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