Aims Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood. Methods and results NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1β-, and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to lipopolysaccharide (LPS) in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD. Conclusions NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodelling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.

中文翻译：

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NOX1 介导小鼠的代谢性心脏病，并在舒张功能障碍的人类单核细胞中上调

目的 微血管炎症在舒张功能障碍 (DD) 和代谢性心脏病的发病机制中起重要作用。NOX1 在血管和免疫细胞中表达，并与代谢性疾病的血管病理学有关。然而，人们对它对代谢性心脏病的贡献知之甚少。方法和结果 NOX1 缺陷小鼠 (KO) 和雄性野生型 (WT) 同窝小鼠被喂食高脂肪高蔗糖饮食 (HFHS) 并注射链脲佐菌素 (75 mg/kg ip) 或对照饮食 (CTD) 和钠柠檬酸盐。尽管体重增加和空腹血糖和胰岛素增加相似，但只有 WT-HFHS 而不是 KO-HFHS 小鼠出现向心性心脏肥大和左心室充盈压升高。这与内皮粘附分子表达增加、Mac-2-、IL-1β-、WT-HFHS 而非 KO-HFHS 心脏中的 NLRP3 阳性细胞和亚硝化应激。Nox1 mRNA 在从健康小鼠心脏中分离出的 CD45+ 免疫细胞中稳定表达，但在心脏 CD31+ 内皮细胞中表达量可忽略不计。然而，在体外，Nox1 表达随着内皮细胞中脂多糖 (LPS) 的增加而增加，并导致 LPS 诱导的 Icam-1 上调。响应于 LPS，Nox1 在小鼠骨髓来源的巨噬细胞中也被上调。在年龄和性别匹配的有症状和无 DD 患者的外周血单核细胞中，与无 DD 患者相比，有 DD 患者的 NOX1 显着更高。结论 NOX1 介导内皮细胞激活并促进小鼠代谢性疾病中的心肌炎症和重塑。鉴于其在患有 DD 的人类单核细胞中的高表达，