ArticleCardiovascular research2022
Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signalling.
Article in Cardiovascular research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Deciphering the rules of regulated cell death subroutines by in silico methods.Journal of advanced research · 2026Review
- Clinical significance of secreted phosphoprotein-1 overexpression in cancers.International journal of clinical oncology · 2026Article
- Mitophagy in Macrophages: A Metabolic Checkpoint in Inflammation-to-Repair Transition in Atherosclerosis.Journal of the American Heart Association · 2026Review
- Myeloid HIF1α has only a minor impact on atherosclerosis development.Vascular biology (Bristol, England) · 2026Article
- Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages.Frontiers in cardiovascular medicine · 2026Review
- A single-cell and spatial atlas of plaque macrophage states in human atherosclerosis.Frontiers in immunology · 2026Review
- Decoding macrophage heterogeneity in the pulmonary fibrosis lung cancer transition.Frontiers in immunology · 2026Review
- Negative Correlation Between Secreted Phosphoprotein 1 and the Treg/Th17 Ratio in Non-Valvular Atrial Fibrillation.Reviews in cardiovascular medicine · 2025Article
- How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia.Nature reviews. Immunology · 2025Review
- Omics-based Approach Towards Macrophages: New Perspectives of Biology and Function in the Normal and Diseased Heart.International journal of biological sciences · 2025Review
- Mechanisms and Prevention Strategies of Macrophage Involvement in the Progression From Hypertension to Heart Failure.International journal of hypertension · 2025Review
- Bridging aging, immunity, and atherosclerosis: novel insights into senescence-related genes.Frontiers in immunology · 2025Article
- Integrating Network Pharmacology and Experimental Validation to Investigate the Action Mechanism of Allicin in Atherosclerosis.Drug design, development and therapy · 2025Article
- Foamy macrophages in atherosclerosis: unraveling the balance between pro- and anti-inflammatory roles in disease progression.Frontiers in cardiovascular medicine · 2025Review
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- Myeloid PHD2 Conditional Knockout Improves Intraplaque Angiogenesis and Vascular Remodeling in a Murine Model of Venous Bypass Grafting.Journal of the American Heart Association · 2024Article
- Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.BMC medicine · 2024Article
- Cellular metabolism changes in atherosclerosis and the impact of comorbidities.Frontiers in cell and developmental biology · 2024Review
- Atherosclerotic plaque vulnerability quantification system for clinical and biological interpretability.iScience · 2023Article
- Single-cell sequencing reveals peritoneal environment and insights into fibrosis in CAPD patients.iScience · 2023Article
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 5 countries.
Funding
Abstract
aimsAtherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis. METHODS AND
resultsMyeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6-12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing 'triggering receptor expressed on myeloid cells-2' (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo.
conclusionMyeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.