Aggressive cholesterol lowering normalizes atherosclerosis regression in Jak2V617F 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.