Disturbed flow regulates protein disulfide isomerase A1 expression via microRNA-204

Area of Science:

• Vascular Biology and Pathophysiology
• Molecular Mechanisms of Disease
• Redox Biology

Background:

• Redox processes significantly influence vascular pathophysiology, with protein disulfide isomerase A1 (PDIA1) playing a complex role in vascular proliferative diseases.
• PDIA1's dual protective and detrimental effects in vascular conditions are cell-type and context-dependent, highlighting the need to understand its regulatory mechanisms.
• Current knowledge regarding the regulation of PDIA1 expression in vascular tissues remains limited, hindering a comprehensive understanding of its role in vascular disease.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling PDIA1 expression in the context of vascular disease.
• To investigate the role of specific microRNAs (miRNAs) as regulators of PDIA1 in vascular cells.
• To determine the functional consequences of PDIA1 regulation by miRNAs on vascular smooth muscle cell (VSMC) differentiation and vascular remodeling.

Main Methods:

• Partial carotid ligation (PCL) model in mice to induce vascular changes and analyze PDIA1 expression.
• Bioinformatic analysis to identify potential miRNA targets of PDIA1, focusing on miR-204-5p and miR-211-5p (miR-204/211).
• In vitro experiments using isolated endothelial cells and VSMCs with miRNA mimics and PDIA1 overexpression/downregulation to assess functional effects on PDIA1 levels and VSMC differentiation markers.

Main Results:

• PDIA1 mRNA and protein levels were significantly upregulated (approximately 5-fold) in vascular layers following PCL.
• miR-204/211 were identified as conserved miRNAs targeting PDIA1 and were found to be downregulated in vascular layers post-PCL.
• miR-204 mimic transfection decreased PDIA1 mRNA in endothelial cells and VSMCs, and importantly, reduced VSMC contractile differentiation markers, an effect reversed by PDIA1 overexpression.

Conclusions:

• A novel regulatory pathway involving miR-204/211 targeting PDIA1 in vascular cells was identified.
• This miR-204-mediated PDIA1 downregulation is functionally relevant in a vascular disease model, impacting VSMC differentiation.
• The identified PDIA1-miRNA regulatory axis represents a potential therapeutic target for vascular proliferative diseases, including atherosclerosis.