Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2 ^V617F Mice

Background

The Jak2 ^V617F ( Jak2 ^VF ) mutation is an important cause of both clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPN). Mouse models of Jak2 ^VF CHIP and MPN show accelerated atherosclerosis progression, driven by macrophage inflammasome activation. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis resolution in Jak2 ^VF mice.

Methods and Results

Chimeric Jak2 ^VF/WT or control WT/WT bone marrow was transplanted into Ldlr ^−/- mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering, there was impaired resolution of lesions in Jak2 ^VF MPN mice compared to controls. However, with marked cholesterol lowering, progression of lesions was halted in both Jak2 ^VF MPN and control mice while macrophage burden was decreased and lesional collagen was increased similarly in Jak2 ^VF MPN and control mice.

Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in Jak2 ^VF macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both Jak2 ^VF and control mice.

Conclusions

Aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2 ^VF MPN, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could reverse atherosclerotic cardiovascular disease (ACVD) risk in individuals with JAK2 ^VF CHIP or MPN.