摘要：

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Myeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/−mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk. •PTP1B inhibition as therapy for atherosclerosis/cardiovascular disease is proposed.•Myeloid-PTP1B mice on ApoE−/−background (ApoE−/−/LysM-PTP1B) were generated.•ApoE−/−/LysM-PTP1B had improved glucose homeostasis with no body weight differences.•ApoE−/−/LysM-PTP1B had lower lipids and protection against atherosclerotic plaques.•Protection was via a PGE2/IL-10/AMPKα mechanism. PTP1B inhibition as therapy for atherosclerosis/cardiovascular disease is proposed. Myeloid-PTP1B mice on ApoE−/−background (ApoE−/−/LysM-PTP1B) were generated. ApoE−/−/LysM-PTP1B had improved glucose homeostasis with no body weight differences. ApoE−/−/LysM-PTP1B had lower lipids and protection against atherosclerotic plaques. Protection was via a PGE2/IL-10/AMPKα mechanism.

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