Aggressive cholesterol lowering normalizes atherosclerosis regression in Jak2V617F mice

TL;DR

Aggressively lowering cholesterol can halt and reverse atherosclerosis in mice with a specific Jak2 mutation, potentially benefiting people with related blood disorders.

Contribution

Demonstrates that aggressive cholesterol reduction halts atherosclerosis in Jak2V617F mice by reversing macrophage inflammation and promoting plaque stability.

Findings

Moderate cholesterol lowering failed to resolve atherosclerosis in Jak2V617F mice, but aggressive lowering halted lesion progression.

Aggressive cholesterol lowering reduced macrophage burden and increased collagen in plaques of both Jak2V617F and control mice.

LDL lowering suppressed inflammation via reduced macrophage proliferation and increased TREM2-expressing macrophages.

Abstract

The Jak2V617F (Jak2VF) mutation is an important cause of both clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPNs). Mouse models of Jak2VF 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 Jak2VF mice. Chimeric Jak2VF/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 Jak2VF MPN mice compared to controls. However, with marked cholesterol lowering, progression of lesions was halted in both Jak2VF MPN and control mice while macrophage burden was decreased and lesional collagen was increased similarly in Jak2VF 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 Jak2VF macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-Myc expressing macrophages in both Jak2VF and control mice. In summary, aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2VF 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 JAK2VF CHIP or MPN.

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