Downregulation of PDCD4 through STAT3/ATF6/autophagy mediates MIF-induced PASMCs proliferation/migration and vascular...

Area of Science:

• Cardiovascular Biology
• Cellular Mechanisms
• Molecular Pathology

Background:

• Pulmonary hypertension (PH) involves pulmonary artery smooth muscle cell (PASMC) proliferation and vascular remodeling.
• The precise molecular pathways driven by macrophage migration inhibitory factor (MIF) in PH remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which MIF induces PASMC proliferation, migration, and vascular remodeling in PH.
• To investigate the role of the signal transducer and activator of transcription 3 (STAT3)/activating transcription factor 6 (ATF6)/autophagy/programmed cell death factor 4 (PDCD4) axis in MIF-mediated PH.

Main Methods:

• Primary cultured rat PASMCs and monocrotaline (MCT)-induced rat PH model were utilized.
• Investigated the effects of MIF on STAT3 phosphorylation, ATF6 activation, autophagy, and PDCD4 levels.
• Employed MIF inhibitor (4-IPP), ATF6 blocker (melatonin), and autophagy inhibitor (chloroquine) for intervention studies.

Main Results:

• MIF promoted PASMC proliferation and migration by increasing STAT3 phosphorylation, activating ATF6, triggering autophagy, and leading to PDCD4 degradation.
• Elevated MIF, p-STAT3, activated ATF6, increased autophagy, and reduced PDCD4 were observed in lung tissues of MCT-induced PH rats.
• Interventions targeting the MIF/STAT3/ATF6/autophagy/PDCD4 pathway effectively suppressed PASMC proliferation and vascular remodeling in PH.

Conclusions:

• MIF activates the STAT3/ATF6/autophagy cascade, resulting in PDCD4 degradation, which drives PASMC proliferation, migration, and pulmonary vascular remodeling in PH.
• The MIF/STAT3/ATF6/autophagy/PDCD4 axis represents a critical pathway in the development of PH.
• Targeting this axis holds potential therapeutic value for managing pulmonary hypertension.