Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and...

Area of Science:

• Cardiovascular Biology
• Immunology
• Cell Biology

Background:

• Blood eosinophil count and eosinophil cationic protein (ECP) concentration are established risk factors for cardiovascular diseases.
• Eosinophils are implicated in inflammatory processes contributing to atherosclerosis.

Purpose of the Study:

• To investigate the role of eosinophils and ECP in vascular calcification and atherogenesis.
• To elucidate the molecular mechanisms by which eosinophils influence smooth muscle cell (SMC) calcification.

Main Methods:

• Immunostaining of human and mouse atherosclerotic lesions to detect eosinophil infiltration.
• Studies using eosinophil-deficient ΔdblGATA mice and wild-type (WT) mice, including adoptive transfer of eosinophils.
• In vitro experiments with SMCs from WT and Runt-related transcription factor-2 (Runx2) knockout mice, treated with eosinophils or mEar1 (mouse homolog of ECP).
• Analysis of signaling pathways (Smad, BMPR, TGFBR) and protein-protein interactions using immunoblotting, immunoprecipitation, and binding assays.
• Correlation analysis of blood eosinophil counts and ECP levels with arterial calcification scores in a human cohort.

Main Results:

• Eosinophil deficiency in ΔdblGATA mice reduced atherogenesis and vascular calcification.
• Eosinophils and mEar1, but not IL-4 or IL-13, induced SMC calcification via the BMPR-1A/1B-Smad-1/5/8-Runx2 pathway.
• mEar1 and human ECP/EDN bound to BMPR-1A/1B on SMCs, promoting osteogenic differentiation.
• Blood eosinophil counts and ECP levels correlated with arterial calcification in a human cohort.

Conclusions:

• Eosinophils contribute to vascular calcification and atherogenesis.
• Eosinophil cationic proteins mediate these effects by activating the BMPR-1A/1B-Smad-1/5/8-Runx2 signaling pathway in SMCs.
• Targeting eosinophils or their cationic proteins may offer therapeutic strategies for cardiovascular diseases.