PMID- 33913468
OWN - NLM
STAT- MEDLINE
DCOM- 20220425
LR  - 20220425
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 118
IP  - 5
DP  - 2022 Mar 25
TI  - Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage 
      apoptosis and paracrine fibrotic signalling.
PG  - 1232-1246
LID - 10.1093/cvr/cvab152 [doi]
AB  - 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) 1alpha/BNIP3 
      axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages 
      (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1alpha/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.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the 
      European Society of Cardiology.
FAU - van Kuijk, Kim
AU  - van Kuijk K
AUID- ORCID: 0000-0001-8880-9039
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
AD  - Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 
      Aachen, Germany.
FAU - Demandt, Jasper A F
AU  - Demandt JAF
AUID- ORCID: 0000-0003-4488-6256
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
FAU - Perales-Paton, Javier
AU  - Perales-Paton J
AD  - Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 
      Aachen, Germany.
AD  - Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg 
      University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany.
AD  - Joint Research Centre for Computational Biomedicine (JRC COMBINE), Faculty of 
      Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Theelen, Thomas L
AU  - Theelen TL
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
FAU - Kuppe, Christoph
AU  - Kuppe C
AD  - Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 
      Aachen, Germany.
FAU - Marsch, Elke
AU  - Marsch E
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
FAU - de Bruijn, Jenny
AU  - de Bruijn J
AUID- ORCID: 0000-0002-2587-9483
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
FAU - Jin, Han
AU  - Jin H
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
FAU - Gijbels, Marion J
AU  - Gijbels MJ
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
AD  - Department of Molecular Genetics, MUMC, Maastricht, Netherlands.
AD  - Department of Experimental Vascular Biology, Amsterdam UMC, Amsterdam, The 
      Netherlands.
AD  - GROW-School for Oncology and Developmental Biology, MUMC, Maastricht, 
      Netherlands.
FAU - Matic, Ljubica
AU  - Matic L
AD  - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, 
      Sweden.
FAU - Mees, Barend M E
AU  - Mees BME
AUID- ORCID: 0000-0001-6545-5813
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Vascular Surgery, MUMC, Maastricht, Netherlands.
FAU - Reutelingsperger, Chris P M
AU  - Reutelingsperger CPM
AUID- ORCID: 0000-0002-2334-9403
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Biochemistry, MUMC, Maastricht, Netherlands.
FAU - Hedin, Ulf
AU  - Hedin U
AUID- ORCID: 0000-0001-9212-3945
AD  - Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, 
      Sweden.
FAU - Biessen, Erik A L
AU  - Biessen EAL
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
AD  - Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, 
      Germany.
FAU - Carmeliet, Peter
AU  - Carmeliet P
AUID- ORCID: 0000-0001-7961-1821
AD  - Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU 
      Leuven, VIB Center for Cancer biology, B-3000 Leuven, Belgium.
FAU - Baker, Andrew H
AU  - Baker AH
AUID- ORCID: 0000-0003-1441-5576
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - BHF Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, 
      UK.
FAU - Kramann, Rafael K
AU  - Kramann RK
AD  - Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 
      Aachen, Germany.
AD  - Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical 
      Center, Rotterdam, The Netherlands.
FAU - Schurgers, Leon J
AU  - Schurgers LJ
AUID- ORCID: 0000-0001-7867-6957
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 
      Aachen, Germany.
AD  - Department of Biochemistry, MUMC, Maastricht, Netherlands.
FAU - Saez-Rodriguez, Julio
AU  - Saez-Rodriguez J
AUID- ORCID: 0000-0002-8552-8976
AD  - Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg 
      University, and Heidelberg University Hospital, Bioquant, Heidelberg, Germany.
AD  - Joint Research Centre for Computational Biomedicine (JRC COMBINE), Faculty of 
      Medicine, RWTH Aachen University, Aachen, Germany.
FAU - Sluimer, Judith C
AU  - Sluimer JC
AUID- ORCID: 0000-0002-0269-4582
AD  - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University 
      Medical Center (MUMC), Maastricht, Netherlands.
AD  - Department of Pathology, MUMC, P. Debyelaan 25, 6229HX Maastricht, Netherlands.
AD  - BHF Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, 
      UK.
LA  - eng
GR  - CH/11/2/28733/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (RNA, Messenger)
RN  - 63231-63-0 (RNA)
RN  - 9007-34-5 (Collagen)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - *Atherosclerosis/metabolism
MH  - Collagen/metabolism
MH  - Fibrosis
MH  - Hypoxia/metabolism
MH  - Macrophages/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - *Plaque, Atherosclerotic/metabolism
MH  - RNA/metabolism
MH  - RNA, Messenger/metabolism
PMC - PMC8953448
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Fibroblasts
OT  - Fibrosis
OT  - Hypoxia
OT  - Inflammation
EDAT- 2021/04/30 06:00
MHDA- 2022/04/26 06:00
PMCR- 2021/04/29
CRDT- 2021/04/29 08:43
PHST- 2020/11/03 00:00 [received]
PHST- 2021/04/23 00:00 [accepted]
PHST- 2021/04/30 06:00 [pubmed]
PHST- 2022/04/26 06:00 [medline]
PHST- 2021/04/29 08:43 [entrez]
PHST- 2021/04/29 00:00 [pmc-release]
AID - 6258177 [pii]
AID - cvab152 [pii]
AID - 10.1093/cvr/cvab152 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2022 Mar 25;118(5):1232-1246. doi: 10.1093/cvr/cvab152.