Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2 ^V617F Mice

Area of Science:

• Cardiovascular Science
• Hematology
• Immunology

Background:

• Clonal hematopoiesis (CH) is an emerging risk factor for atherosclerotic cardiovascular disease (ACVD).
• CH promotes atherosclerosis progression via macrophage inflammatory responses.
• The impact of inflammation on atherosclerosis regression in CH remains unclear.

Purpose of the Study:

• To investigate whether ongoing inflammation impedes atherosclerosis regression in JAK2 V617F (JAK2 VF) CH mice.
• To assess the effect of different low-density lipoprotein (LDL) lowering intensities on plaque regression in CH mice.

Main Methods:

• Bone marrow transplantation of JAK2 VF or control WT into Ldlr-/- mice.
• Induction of atherosclerosis with a Western diet, followed by moderate or marked LDL cholesterol lowering.
• Analysis of plaque regression and macrophage inflammatory markers.

Main Results:

• Moderate LDL lowering showed impaired regression in JAK2 VF CH mice compared to controls.
• Marked LDL lowering resulted in similar regression in both JAK2 VF CH and control mice.
• Aggressive LDL lowering reversed inflammasome activation and induced pro-resolving macrophage changes in JAK2 VF CH mice.

Conclusions:

• Aggressive LDL cholesterol lowering effectively reverses inflammasome activation and promotes plaque stabilization in JAK2 VF CH.
• These findings suggest that intensive LDL lowering may mitigate ACVD risk in individuals with JAK2 VF clonal hematopoiesis.