An NRIP1-Centric Monocyte Immunogenetic Bridge Between Heart Failure and Ischemic Stroke
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Background Heart failure (HF) and ischemic stroke (IS) frequently co-occur and worsen each other. Circulating immune cells may act as a cross-organ inflammatory bridge, but the key immune lineage, genetically supported mediators, and druggable targets remain unclear. Objective To identify the immune-cell lineage, candidate gene, and tractable intervention target linking HF and IS. Methods Bidirectional Mendelian randomization (MR) of genome-wide association study summary statistics was used to assess causal links between HF and IS. Mouse single-cell transcriptomic datasets from HF and IS models were integrated to define a shared immune/stromal atlas and characterize Ly6C⁺ monocyte expansion. Ly6C⁺ monocyte marker genes were mapped to human orthologs and evaluated using peripheral-blood expression quantitative trait locus data for gene-level MR, followed by expression validation, colocalization, summary-data–based MR, and spatial transcriptomics. In HF single-cell data, Ly6C⁺ monocytes were stratified by Nrip1 expression for cell–cell communication, pathway enrichment, and pseudotime analyses. Candidate-drug prediction, druggability evaluation, molecular docking, molecular dynamics simulation, and in vitro validation were then performed. Results MR supported a bidirectional positive association between HF and IS. Both diseases showed expansion of inflammatory Ly6C⁺ monocytes at single-cell resolution. Among MR-implicated genes, NRIP1 was prioritized as a key gene associated wi
Abstract
Background Heart failure (HF) and ischemic stroke (IS) frequently co-occur and worsen each other. Circulating immune cells may act as a cross-organ inflammatory bridge, but the key immune lineage, genetically supported mediators, and druggable targets remain unclear. Objective To identify the immune-cell lineage, candidate gene, and tractable intervention target linking HF and IS. Methods Bidirectional Mendelian randomization (MR) of genome-wide association study summary statistics was used to assess causal links between HF and IS. Mouse single-cell transcriptomic datasets from HF and IS models were integrated to define a shared immune/stromal atlas and characterize Ly6C⁺ monocyte expansion. Ly6C⁺ monocyte marker genes were mapped to human orthologs and evaluated using peripheral-blood expression quantitative trait locus data for gene-level MR, followed by expression validation, colocalization, summary-data–based MR, and spatial transcriptomics. In HF single-cell data, Ly6C⁺ monocytes were stratified by Nrip1 expression for cell–cell communication, pathway enrichment, and pseudotime analyses. Candidate-drug prediction, druggability evaluation, molecular docking, molecular dynamics simulation, and in vitro validation were then performed. Results MR supported a bidirectional positive association between HF and IS. Both diseases showed expansion of inflammatory Ly6C⁺ monocytes at single-cell resolution. Among MR-implicated genes, NRIP1 was prioritized as a key gene associated with reduced IS risk, and genetic and spatial evidence supported its monocyte-mediated role in HF–IS coupling. Nrip1-stratified and pseudotime analyses suggested a homeostatic role through modulation of inflammatory thresholds and communication patterns. Drug prediction and in silico analyses indicated that retinoic acid–related small molecules may bind NRIP1 and exhibit preliminary druggability. In vitro, tretinoin alleviated ischemia-like HMC3 cell injury and inflammation by modulating monocyte NRIP1. Conclusion An NRIP1-centered monocyte network may represent a tractable immune bridge in HF–IS comorbidity, and tretinoin provides an entry point for NRIP1-targeted intervention. Graphical Abstract The graphical abstract summarizes the study framework and proposed mechanism linking HF and IS through Ly6C⁺ monocytes and NRIP1. It illustrates the integration of MR, scRNA-seq, gene-level MR, colocalization, SMR, spatial transcriptomics, and cell–cell communication analyses to identify NRIP1 as a key gene. It also shows candidate-drug prediction, molecular docking, molecular dynamics simulation, and in vitro validation of retinoic acid-related candidate interventions. A graphical abstract summarizing an NRIP1-centered Ly6C⁺ monocyte immune bridge between HF and IS and the evaluation of retinoic acid-related candidate interventions. http://www.w3.org/1999/xlink print-only float portrait JIR-19-613632-g0001.jpg anchor uf0001 portrait graphical