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The association of cardiovascular health with new-onset pulmonary hypertension and the mediating role of proteomic signatures.

Meng-Jie Zhang·Ya-Cong Bo·Jun-Zhuo Shi·Ming-Dan Xu·Xiang-Ying Suo·Cui-Cui Chen·Meng-Tong Xu·Lu-Ling Zhao·Hong-Da Zhang·Jie-Jian Kou·Xin-Mei Xie·Xiao-Bin Pang·Yong-Jian Zhu·Yi Yan·Yang-Yang He
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Abstract

BACKGROUND: The cardiovascular health (CVH) metrics have been reported to play an important role in the development of noncommunicable chronic diseases, yet its link to pulmonary hypertension (PH) risk and the underlying biological mechanisms remain unclear. This study aimed to investigate the association of CVH with PH risk and elucidate the mediating role of plasma proteomic signatures. METHODS: A total of 279 220 participants without PH at enrollment of the UK Biobank were included. Cox regression was used to quantify the association between CVH and incident PH. Proteome-wide association analysis, mediation analysis, and functional enrichment analysis were conducted to identify protein mediators. Key hub proteins were further validated at the transcriptional level through quantitative polymerase chain reaction (qPCR) in an animal model of PH, as well as at the protein level, and by macrophage-specific knockdown of interleukin (IL)-6 and CCL4 to evaluate its impact on rat pulmonary artery smooth muscle cell (PASMC) migration and proliferation. RESULTS: Over a median 13.2-year follow-up, 1325 PH cases occurred. Compared to the lowest CVH, participants with moderate and high CVH had 59% [hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.33-0.49] and 82% (HR: 0.18; 95% CI: 0.14-0.23) lower risk, respectively. Proteomic analyses revealed that this association was significantly mediated by a distinct plasma protein signature. Pathway enrichment analysis indicates that proteins are significantly enriched in inflammatory/immune pathways, and key hub proteins were identified as participating in the central mechanism pathway. In the lung tissue of PH rat models, the mRNA and protein expression levels of IL-6 and C-C motif chemokine ligand 4 (CCL4) were significantly elevated. Furthermore, functional assays demonstrated that knockdown of IL-6 or CCL4 in macrophages significantly attenuated the migration and proliferation of rat PASMCs in vitro. CONCLUSION: High CVH level, defined by Life's Essential 8 (LE8), is significantly linked to a reduced risk of developing PH. This protective effect is primarily mediated by a proteomic signature, revealing the role of signaling pathways such as cytokine-cytokine receptor interaction in the prevention of PH.

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Hypertension, PulmonaryHumansProteomicsAnimalsMaleRatsFemaleMiddle AgedMyocytes, Smooth MuscleCell ProliferationAgedInterleukin-6Muscle, Smooth, VascularLife's Essential 8cardiovascular healthmediation analysisproteomicspulmonary hypertensionJournal ArticleResearch Support, Non-U.S. Gov't

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Meng-Jie Zhang, Ya-Cong Bo, Jun-Zhuo Shi, Ming-Dan Xu, Xiang-Ying Suo, Cui-Cui Chen, Meng-Tong Xu, Lu-Ling Zhao, Hong-Da Zhang, Jie-Jian Kou, Xin-Mei Xie, Xiao-Bin Pang, Yong-Jian Zhu, Yi Yan, Yang-Yang He. 2026-07-27. The association of cardiovascular health with new-onset pulmonary hypertension and the mediating role of proteomic signatures.. https://doi.org/10.1097/hjh.0000000000004409

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Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗