Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

中文翻译：

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IRS2失调在缺氧条件下肺血管重塑中的炎症作用

肺动脉高压（PH）是一种破坏性疾病，其特征是肺血管阻力进行性升高、右心室衰竭，并最终导致死亡。我们之前已经证明，胰岛素受体底物 2 (IRS2) 是一种对胰岛素抵抗和代谢非常关键的分子，在 Th2 偏向的肺部炎症和肺血管重塑中具有抗炎作用。在这里，我们研究了 IRS2 在人类和实验性 PH 中具有免疫调节作用的假设。表达分析表明，IRS2 在肺动脉高压患者和 PH 大鼠模型的肺血管系统中显着降低。在小鼠中，IRS2 的基因消融增强了肺组织中缺氧诱导的 Akt 和 Forkhead box O1 (FOXO1) 信号通路，并增加了肺血管肌肉化、增殖和血管周围巨噬细胞的募集。此外，纯合IRS2基因缺失的小鼠在缺氧反应中表现出显着的基因剂量依赖性肺血管重塑和右心室肥厚增加。对从 IRS2 基因缺失纯合子小鼠中分离的骨髓源性巨噬细胞进行的功能研究表明，缺氧暴露导致 Akt 和 ERK 信号通路增强，随后 pro-PH 巨噬细胞激活标记物血管内皮生长因子-A 和精氨酸酶 1 增加我们的数据表明，IRS2 通过调节巨噬细胞的激活和募集来发挥抗炎作用，这可能会限制 PH 病理学中出现的血管炎症、重塑和右心室肥大。恢复IRS2通路可能是治疗PH和右心衰竭的有效治疗方法。