RESUMEN
BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.
Asunto(s)
Proteínas de la Matriz Extracelular , Pulmón , Hipertensión Arterial Pulmonar , Humanos , Animales , Pulmón/metabolismo , Pulmón/patología , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/genética , Ratas , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Masculino , Estudio de Asociación del Genoma Completo , Redes Reguladoras de Genes , Transducción de Señal , Perfilación de la Expresión Génica , Proteína smad3/metabolismo , Proteína smad3/genética , Femenino , Ratas Sprague-Dawley , Proteína Smad2/metabolismo , Proteína Smad2/genética , Transcriptoma , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de los fármacos , Persona de Mediana Edad , MultiómicaRESUMEN
This review examines how single-cell omics technologies, particularly single-cell RNA sequencing (scRNAseq), enhance our understanding of pulmonary arterial hypertension (PAH). PAH is a multifaceted disorder marked by pulmonary vascular remodeling, leading to high morbidity and mortality. The cellular pathobiology of this heterogeneous disease, involving various vascular and non-vascular cell types, is not fully understood. Traditional PAH studies have struggled to resolve the complexity of pathogenic cell populations. scRNAseq offers a refined perspective by detailing cellular diversity within PAH, identifying unique cell subsets, gene networks, and molecular pathways that drive the disease. We discuss significant findings from recent literature, summarizing how scRNAseq has shifted our understanding of PAH in human, rat, and mouse models. This review highlights the insights gained into cellular phenotypes, gene expression patterns, and novel molecular targets, and contemplates the challenges and prospective paths for research. We propose ways in which single-cell omics could inform future research and translational efforts to combat PAH.