Abstract
ObjectiveCardiovascular 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. MethodsWe 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. ResultsMyeloid-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. ConclusionsHere 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.
Highlights
Despite extensive research and major advancements in modern medicine, Cardiovascular disease (CVD) are still the leading cause of death worldwide accounting for 17.3 million deaths globally per year (WHO Statistics, http://www.who.int/mediacentre/factsheets/fs317/en/)
Myeloid specific protein tyrosine phosphatase 1B (PTP1B) knockout mice exhibit improved glucose homeostasis independently of alterations in body weight/ adiposity We recently demonstrated that myeloid PTP1B (LysM PTP1B) deletion protected against LPS-induced inflammation and led to increased production of the anti-inflammatory cytokine interleukin 10 (IL-10) [14]
Despite no differences in weight gain, ApoEÀ/À/LysM-PTP1B animals exhibited markedly improved glucose tolerance when compared to ApoEÀ/À, which was more pronounced in the female mice (Figure 2 A, B)
Summary
Despite extensive research and major advancements in modern medicine, CVDs are still the leading cause of death worldwide accounting for 17.3 million deaths globally per year (WHO Statistics, http://www.who.int/mediacentre/factsheets/fs317/en/) Such diseases are exacerbated by obesity and secondary pathologies such as Type 2 diabetes and atherosclerosis [1]; it is not surprising that the number of deaths attributed to CVDs is expected to rise within the decade. Decreased insulin signaling in nonhematopoietic cells, as achieved by transplantation of ApoEÀ/À mouse model of atherosclerosis with bone marrow cells from IRS1þ/À IRþ/À ApoEÀ/À mice, contributed to increased atherogenesis in these mice [4] In all these disorders, macrophages play a key role driving the pathology [6e9]; targeting their activity could prove effective. We used the ApoEÀ/À mouse model of atherosclerosis under physiological and atherogenic conditions
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