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Insulin Receptor Substrate 2 is Decreased in Clinical Pulmonary Hypertension and Its Anti-Inflammatory Role in the Pulmonary Vasculature Under Hypoxic Conditions

K Yamaji-Kegan

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1008

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Pulmonary arterial hypertension (PAH) 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. Here, we investigated the role of IRS2 in human PAH. We also analyzed the role of IRS2 in pulmonary vascular remodeling in mice under hypoxic conditions.

Methods

We analyzed the IRS2 expression in the remodeling pulmonary vasculature in the patients with idiopathic PAH (IPAH). We compared the degree of hypoxia-induced pulmonary vascular remodeling between wild-type (IRS2 +/+) and IRS2 heterozygous-knockout (IRS2 +/-) mice in vivo.

Results

We observed dysregulated IRS2 expression in the pulmonary vasculature of patients with IPAH as compared to healthy control subjects. In our preliminary studies, IRS2+/- mice showed dramatic increases in fully muscularized pulmonary vessels accompanied by accumulation of RELMα-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. We also observed that IRS2 knockdown resulted in exaggerated proliferative activities in the pulmonary vasculature as compared to IRS2+/+ mice in response to hypoxia

Conclusions

Our results suggest that IRS2 expression is dysregulated in clinical PAH. It also suggests that IRS2 possesses anti-inflammatory properties by regulating MΦ activation and recruitment which may limit vascular inflammation and a hyper-proliferative microenvironment that are seen in PAH pathology. Restoring IRS pathway in humans may be an effective immunosuppressive therapy for the treatment of PAH.