Impaired CAMK4 Activity Limits Atherosclerosis and Reprograms Myelopoiesis

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Chronic inflammation significantly drives atherosclerotic cardiovascular disease.
• Increased calcium/calmodulin-dependent protein kinase IV (CaMK4) expression is observed in human atherosclerotic plaques.
• CaMK4 is elevated in plaque macrophages, suggesting a role in atherosclerosis.

Purpose of the Study:

• To investigate the role of CaMK4 in promoting inflammation and impairing resolution in atherosclerosis.
• To determine if CaMK4 regulates the myelopoietic response to hypercholesterolemia.

Main Methods:

• Generated knockout mice lacking functional CaMK4 (Camk4-/-).
• Induced hypercholesterolemia using AAV8-PCSK9 and a high-fat/high-cholesterol diet.
• Analyzed lesion size, stability, monocyte populations, and myeloid progenitor levels.

Main Results:

• Camk4-/- mice exhibited smaller, more stable atherosclerotic lesions.
• Loss of CaMK4 resulted in peripheral monocytosis with a less inflammatory monocyte subset.
• Camk4-/- monocytes showed altered gene expression (ATF6, Nr4a1) and impaired trafficking, with macrophages displaying a pro-reparative phenotype.

Conclusions:

• CaMK4 regulates myelopoiesis during hypercholesterolemia via ATF6-mediated transcription.
• Loss of CaMK4 promotes a pro-reparative phenotype in myeloid cells.
• Targeting CaMK4 presents a potential therapeutic strategy for atherosclerosis.