Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signalling.

Autor:	van Kuijk K; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany., Demandt JAF; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands., Perales-Patón J; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany.; Joint Research Centre for Computational Biomedicine (JRC COMBINE), Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Theelen TL; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands., Kuppe C; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany., Marsch E; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands., de Bruijn J; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands., Jin H; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands., Gijbels MJ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.; Department of Molecular Genetics, MUMC, Maastricht, Netherlands.; Department of Experimental Vascular Biology, Amsterdam UMC, Amsterdam, The Netherlands.; GROW-School for Oncology and Developmental Biology, MUMC, Maastricht, Netherlands., Matic L; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden., Mees BME; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Vascular Surgery, MUMC, Maastricht, Netherlands., Reutelingsperger CPM; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Biochemistry, MUMC, Maastricht, Netherlands., Hedin U; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden., Biessen EAL; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany., Carmeliet P; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, VIB Center for Cancer biology, B-3000 Leuven, Belgium., Baker AH; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; BHF Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, UK., Kramann RK; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands., Schurgers LJ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.; Department of Biochemistry, MUMC, Maastricht, Netherlands., Saez-Rodriguez J; Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany.; Joint Research Centre for Computational Biomedicine (JRC COMBINE), Faculty of Medicine, RWTH Aachen University, Aachen, Germany., Sluimer JC; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC), Maastricht, Netherlands.; Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.; BHF Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, UK.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2022 Mar 25; Vol. 118 (5), pp. 1232-1246.
DOI:	10.1093/cvr/cvab152
Abstrakt:	Aims: Atherosclerotic 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 Results: Myeloid-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. Conclusion: Myeloid 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. (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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