Irisin Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension via Ubiquitin-Mediated Regulation of ENO1

Pulmonary vascular remodeling, which current therapeutic targets fail to alleviate disease severity, plays a key role in pulmonary arterial hypertension (PAH). Irisin is identified as a protective factor involved in regulating inflammation and oxidative stress, but its role in PAH remains unknown. To investigate, plasma irisin levels and its local pulmonary artery expression are measured in patients with PAH and mouse models. Irisin expression is significantly decreased in patients with PAH and PAH mouse models. Furthermore, overexpression and exogenous injection of irisin effectively alleviate hemodynamic and right-heart function in PAH mouse models, meanwhile, it also reverses proliferation and cell cycle progression of pulmonary artery smooth muscle cells (PASMCs). To illustrate the mechanism of irisin exerts on PAH, Enolase 1 is identified as a key irisin-interacting protein. Irisin suppresses proliferation of PDGF-induced PASMCs by promoting ubiquitination status of Enolase 1 via E3 ligase of down regulated protein 4 in neural precursor cell development. Co-immunoprecipitation and molecular docking analyses verifies the interaction and binding sites between irisin and its interactive proteins. Overall, these findings suggest that, irisin is a novel protective factor downregulated in PAH. By ubiquitination, irisin promotes Enolase 1 degradation and suppresses cell proliferation and pulmonary vascular remodeling in PAH.