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Anti-Inflammatory Properties of Insulin Receptor Substrate Protein in Macrophages Under Hypoxic Conditions

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A4625 - Anti-Inflammatory Properties of Insulin Receptor Substrate Protein in Macrophages Under Hypoxic Conditions
Author Block: K. Kegan, R. A. Johns; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Rationale: Pulmonary hypertension (PH) is a devastating disease characterized by a progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. Recently, an important association between insulin resistance and PH has been identified. Both conditions occur in the presence of chronic inflammation and vascular dysfunction. We have found previously that insulin receptor substrate 2 (IRS2), one of the most critical molecules to insulin resistance and cellular energy homeostasis, plays a critical anti-inflammatory role in macrophage (Mφ) activation in Th2-skewed lung inflammation and pulmonary vascular remodeling. Genetic ablation of IRS2 in mice exacerbated perivascular Mφ recruitment and muscularization of pulmonary artery smooth muscle cells. Here, we investigated the role of IRS2 in Mφ activation under hypoxic conditions.
Methods: We compared the degree of hypoxia-induced pulmonary vascular remodeling between wild-type (IRS2+/+) and IRS2 heterozygous-knockout (IRS2+/-) mice in vivo. We also examined the expression of Mφ markers using bone marrow (BM) Mφ isolated from IRS2+/+ and IRS2 homozygous (IRS2-/-) mice in response to Th2 cytokine IL-4 or hypoxia in vitro.
Results: In our preliminary studies, IRS2 heterozygous (IRS2+/-) mice showed dramatic increases in fully muscularized pulmonary vessels accompanied by accumulation of RELMα/FIZZ1-expressing Mφ at day 4 of hypoxia stimulation. To our surprise, pulmonary vessels were fully muscularized in IRS2+/- mice at day 4 of hypoxia, whereas full muscularization usually requires 3 weeks in mice. In addition, our data show that both Th2 cytokine IL-4 and hypoxia promote significant decreases in IRS2 gene transcription in BMMφ, suggesting that those stimuli may cause impaired IRS2 expression and function in this cell type. Furthermore, IL-4- or hypoxia-induced expression of pro-PH Mφ activation markers VEGF-A and Arg1 were significantly increased in BMMΦ isolated from IRS2-/- mice as compared to IRS2+/+ BMMΦ.
Conclusions: Our results suggest that IRS2 possesses anti-inflammatory properties by regulating Mφ activation and its function which may limit vascular inflammation and a hyper-proliferative microenvironment that are seen in PH pathology. Restoring IRS pathway in humans may be an effective immunosuppressive therapy for the treatment of PH.
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