Biology subjects

Leeper, N. J.

Publications and source records attributed to Leeper, N. J..

4 recordsLinked to original sources

bioRxiv2026

CD47 Blockade Reprograms the Monocyte-Macrophage Axis to Promote Inflammation Resolution in Atherosclerosis

Atherosclerosis is a chronic inflammatory disease and a leading cause of cardiovascular mortality worldwide. Disease progression is closely linked to defective efferocytosis, the impaired clearance of apoptotic cells, which drives necrotic core expansion and perpetuates arterial inflammation. Targeting the CD47-SIRP innate immune checkpoint, a dominant "dont-eat-me" signal, limits atherosclerosis in preclinical models and retrospective human studies. However, how pro-efferocytic intervention reshapes the immune landscape of established atherosclerotic lesions remains incompletely understood. Here, using single-cell transcriptomics, monocyte fate mapping, and functional analyses across complementary preventive and interventive murine atherosclerosis models, we demonstrate that CD47 blockade fundamentally reprograms the myeloid landscape of established lesions. Anti-CD47 therapy selectively suppresses inflammatory Ly6Chi monocyte recruitment and reduces local macrophage proliferation without altering overall plaque macrophage burden, indicating a qualitative rather than quantitative remodeling of the infiltrate. Concurrently, therapy enriches macrophage subsets bearing pro-efferocytic and macrophage survival-associated transcriptional programs, restoring defective apoptotic cell clearance in situ. Cross-species integration with an independent human coronary artery single-cell dataset identifies a conserved TREM2hi macrophage population that natively harbors the efferocytosis machinery reactivated by therapy in mice. Together, these findings demonstrate that innate immune checkpoint inhibition by CD47 blockade drives a coordinated reprogramming of monocyte-macrophage dynamics, simultaneously suppressing inflammatory influx and enriching efferocytic capacity. This dual mechanism advances our understanding of how pro-efferocytic therapies resolve vascular inflammation in atherosclerosis.

cell biology↗

bioRxiv2026

Cancer drives atherosclerotic plaque vulnerability by inducing pathological angiogenesis

Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF- induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.

pathology↗

bioRxiv2021

Cell-specific chromatin landscape of human coronary artery resolves regulatory mechanisms of disease risk

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across several cell types. Genome-wide association studies (GWAS) have identified over 170 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-cell ATAC-seq to profile 28,316 cells across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants via quantitative trait locus and sequence-based predictive modeling. We identified a number of candidate mechanisms for smooth muscle cell transition states and identified putative binding sites for risk variants. We further employed CRE to gene linkage to nominate disease-associated key driver transcription factors such as PRDM16 and TBX2. This single cell atlas provides a critical step towards interpreting cis-regulatory mechanisms in the vessel wall across the continuum of CAD risk.

genomics↗

bioRxiv2017

Bioimpedance and new onset heart failure: A longitudinal study of ~500,000 individuals from the general population

ImportanceHeart failure constitutes a high burden on patients and society, but although lifetime risk is high, it is difficult to predict without costly or invasive testing. Knowledge about novel risk factors could enable early diagnosis and possibly preemptive treatment.\n\nObjectiveTo establish new risk factors for heart failure.\n\nDesignWe applied supervised machine learning in UK Biobank in an agnostic search of risk factors for heart failure. Novel predictors were then subjected to several in-depth analyses, including multivariable Cox models of incident heart failure, and assessment of discrimination and calibration.\n\nSettingPopulation-based cohort study.\n\nParticipants500,451 individuals who volunteered to participate in the UK Biobank cohort study, excluding those with prevalent heart failure.\n\nExposure3646 variables reflecting different aspects of lifestyle, health and disease-related factors.\n\nMain OutcomeIncident heart failure hospitalization.\n\nResultsMachine learning confirmed many known and putative risk factors for heart failure, and identified several novel candidates. Mean reticulocyte volume appeared as one novel factor, and leg bioimpedance another; the latter appearing as the most important new factor. Leg bioimpedance was significantly lower in those who developed heart failure (p=1.1x10-72) during up to 9.8-year follow-up. When adjusting for known heart failure risk factors, leg bioimpedance was inversely related to heart failure (hazard ratio [95%CI], 0.60 [0.48-0.73]) and 0.75 [0.59-0.94], in age- and sex-adjusted and fully adjusted models, respectively, comparing the upper vs. lower quartile). A model including leg bioimpedance, age, sex, and self-reported history of myocardial infarction showed good predictive capacity of future heart failure hospitalization (C-index=0.82) and good calibration.\n\nConclusions and RelevanceLeg bioimpedance is inversely associated with heart failure incidence in the general population. A simple model of exclusively non-invasive measures, combining leg bioimpedance with history of myocardial infarction, age, and sex provides accurate predictive capacity.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhich are the most important risk factors for incident heart failure?\n\nFindingsIn this population-based cohort study of ~500,000 individuals, machine learning identified well-established risk factors, but also several novel factors. Among the most important were leg bioimpedance and mean reticulocyte volume. There was a strong inverse relationship between leg bioimpedance and incident heart failure, also in adjusted analyses. A model entailing leg bioimpedance, age, sex, and self-reported history of myocardial infarction showed good predictive capacity of heart failure hospitalization and good calibration.\n\nMeaningLeg bioimpedance appears to be an important new factor associated with incident heart failure.

epidemiology↗