Aggressive cholesterol lowering normalizes atherosclerosis regression in Jak2^V617F mice

The Jak2^V617F (Jak2^VF) mutation is an important cause of both clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPNs). 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. 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. In summary, 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 risk in individuals with JAK2^VF CHIP or MPN.