Abstract
Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due toaccelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulinreceptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulinresistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of theIR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.
Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, biochemical and targeted lipidomic eicosanoid analyses were performed.
Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.
Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.
Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, biochemical and targeted lipidomic eicosanoid analyses were performed.
Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.
Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.
| Original language | English |
|---|---|
| Pages (from-to) | 845-853 |
| Journal | Molecular Metabolism |
| Volume | 6 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Jun 2017 |
