Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque...

Area of Science:

• Cardiovascular Research
• Immunology
• Molecular Biology

Background:

• Leukocyte migration is crucial for inflammatory processes, including monocyte infiltration and macrophage accumulation.
• Hck (hematopoietic cell kinase) and Fgr (Fgr tyrosine kinase) play significant roles in leukocyte migration.
• Their specific impact on atherosclerosis, lesion inflammation, and stability warrants investigation.

Purpose of the Study:

• To evaluate the impact of hematopoietic deficiency of Hck and Fgr on atherosclerosis development.
• To assess the effects of Hck/Fgr deficiency on atherosclerotic lesion inflammation and stability.
• To understand the mechanisms underlying Hck/Fgr's role in monocyte function and migration within atherosclerotic plaques.

Main Methods:

• Generation of hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeric mice via bone marrow transplantation.
• Assessment of atherosclerotic lesion size, stability, macrophage content, cap thickness, and necrotic core expansion.
• In vitro and in vivo evaluation of myeloid cell adhesion and transmigration across endothelial monolayers and atherosclerotic plaques using intravital microscopy, flow cytometry, and histology.
• Analysis of macrophage podosome formation and mesenchymal migration capacity.

Main Results:

• Hck/Fgr deficiency resulted in smaller atherosclerotic lesions, but these lesions were paradoxically less stable, exhibiting cap thinning and expanded necrotic cores.
• Despite a pro-inflammatory monocyte phenotype, Hck/Fgr deficiency disrupted myeloid cell adhesion and transmigration.
• Hck/Fgr-deficient macrophages displayed impaired podosome formation and migration, leading to subendothelial accumulation and potential plaque erosion.

Conclusions:

• Hematopoietic deficiency of Hck and Fgr attenuates atherosclerotic plaque formation by inhibiting endothelial adhesion and transmigration.
• Conversely, Hck/Fgr deficiency promotes plaque instability through monocyte subset imbalance and subendothelial accumulation.
• Targeting src kinases like Hck and Fgr for intervention in plaque inflammation requires caution due to paradoxical effects on plaque stability.