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Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.
Meng, Zhaojie; Zhang, Shuya; Li, Wei; Wang, Yunzhe; Wang, Minjie; Liu, Xin; Liu, Cong-Lin; Liao, Sha; Liu, Tianxiao; Yang, Chongzhe; Lindholt, Jes S; Rasmussen, Lars M; Obel, Lasse M; Stubbe, Jane; Diederichsen, Axel C; Sun, Yong; Chen, Yabing; Yu, Paul B; Libby, Peter; Shi, Guo-Ping; Guo, Junli.
Affiliation
  • Meng Z; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Zhang S; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Li W; Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research & Key Laboratory of Emergency and Trauma of Ministry of Education, Institute of Cardiovascular Research of the First Affiliated Hospital, Hainan Medical University, Haikou 571199, Hainan, China.
  • Wang Y; College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, Jilin, China.
  • Wang M; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Liu X; Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Liu CL; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Liao S; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Liu T; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Yang C; Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Lindholt JS; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Rasmussen LM; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Obel LM; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
  • Stubbe J; Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510000, Guangdong, China.
  • Diederichsen AC; Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark.
  • Sun Y; Elite Research Centre of Individualized Treatment for Arterial Disease, University Hospital, Odense, Denmark.
  • Chen Y; Elite Research Centre of Individualized Treatment for Arterial Disease, University Hospital, Odense, Denmark.
  • Yu PB; Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark.
  • Libby P; Elite Research Centre of Individualized Treatment for Arterial Disease, University Hospital, Odense, Denmark.
  • Shi GP; Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark.
  • Guo J; Cardiovascular and Renal Research unit, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Eur Heart J ; 44(29): 2763-2783, 2023 08 01.
Article in En | MEDLINE | ID: mdl-37279475
ABSTRACT

AIMS:

Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND

RESULTS:

Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries.

CONCLUSION:

Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Atherosclerosis / Vascular Calcification Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Eur Heart J Year: 2023 Type: Article Affiliation country: United States
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Atherosclerosis / Vascular Calcification Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Eur Heart J Year: 2023 Type: Article Affiliation country: United States