The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions.

Abstract

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.

• Authors: Mayumi Nakahara, Homare Ito, John T Skinner, Qing Lin, Rasa Tamosiuniene, Mark R Nicolls, Achsah D Keegan, Roger A Johns, Kazuyo Yamaji-Kegan
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 321 Issue 2 Pg. L416-L428 (08 01 2021) ISSN: 1522-1504 [Electronic] United States
• PMID: 34189964 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• FOXO1 protein, human
• Forkhead Box Protein O1
• Foxo1 protein, mouse
• IRS2 protein, human
• Insulin Receptor Substrate Proteins
• Irs2 protein, mouse
• Irs2 protein, rat
• Nerve Tissue Proteins
• Foxo1 protein, rat
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Disease Models, Animal
• Female
• Forkhead Box Protein O1 (genetics, metabolism)
• Humans
• Hypertension, Pulmonary (genetics, metabolism, pathology)
• Hypoxia (genetics, metabolism, pathology)
• Inflammation (genetics, metabolism, pathology)
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Rats
• Rats, Nude
• Vascular Remodeling