ITLN1 Improves Endothelial Dysfunction in Hypertensive Mice via Wnt5b-JNK Signaling

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Medicine

Background:

• Hypertension is a common cardiovascular disease linked to endothelial cell dysfunction.
• Intelectin-1 (ITLN1), a secreted adipokine, is known to promote vasodilation, but its precise mechanisms are unclear.

Purpose of the Study:

• To investigate the role of ITLN1 in endothelial function and hypertension.
• To elucidate the molecular pathways through which ITLN1 influences vascular homeostasis.
• To identify potential therapeutic agents that modulate ITLN1 activity.

Main Methods:

• Generated endothelial-specific ITLN1 knockout mice to assess ITLN1 deficiency effects.
• Employed RNA sequencing, qPCR, immunoblotting, immunofluorescence, and nitric oxide quantification.
• Utilized virtual molecular docking to identify ITLN1-binding compounds.

Main Results:

• Hypertensive mice showed reduced ITLN1 levels and impaired vasodilation.
• ITLN1 overexpression improved vascular relaxation in hypertensive models.
• ITLN1 suppressed Wnt5b-JNK signaling, restoring eNOS phosphorylation and nitric oxide production.
• Puerarin 6-O-xyloside was identified as an ITLN1 activator, and ZNF460 as a repressor.

Conclusions:

• ITLN1 is a potential therapeutic target for hypertension.
• Modulating Wnt5b-JNK/eNOS signaling via ITLN1 upregulation ameliorates endothelial dysfunction.
• Puerarin 6-O-xyloside shows promise as an ITLN1-activating therapeutic agent.