Aggressive cholesterol lowering normalizes atherosclerosis regression in Jak2^V617F mice.

Area of Science:

• Cardiovascular Biology
• Hematology
• Immunology

Background:

• The JAK2^V617F (JAK2^VF) mutation drives clonal hematopoiesis and myeloproliferative neoplasms (MPN).
• JAK2^VF CHIP and MPN models exhibit accelerated atherosclerosis due to macrophage inflammasome activation.
• Ongoing inflammation is hypothesized to impede atherosclerosis resolution in JAK2^VF mice.

Purpose of the Study:

• To assess if ongoing inflammation impedes atherosclerosis resolution in JAK2^VF mice.
• To investigate the impact of LDL cholesterol lowering on atherosclerosis in JAK2^VF MPN models.
• To elucidate the mechanisms by which LDL lowering affects plaque inflammation and stability.

Main Methods:

• Chimeric JAK2^VF/WT or WT/WT bone marrow transplanted into Ldlr^-/- mice.
• Western diet-induced atherosclerosis followed by moderate or marked LDL cholesterol lowering.
• Analysis of lesion progression, macrophage burden, collagen content, and molecular markers of inflammation and macrophage activation.

Main Results:

• Moderate LDL lowering impaired lesion resolution in JAK2^VF MPN mice compared to controls.
• Marked LDL lowering halted lesion progression in both JAK2^VF MPN and control mice.
• LDL lowering reversed JAK2^VF macrophage inflammasome activation and increased TREM2 and c-Myc expression.

Conclusions:

• Aggressive LDL lowering reverses inflammasome activation and promotes pro-resolving macrophage changes in JAK2^VF MPN.
• Intensive LDL cholesterol reduction halts atherosclerosis progression and stabilizes plaques in JAK2^VF MPN.
• Aggressive LDL lowering may reverse atherosclerotic cardiovascular disease risk in individuals with JAK2^VF CHIP or MPN.