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

BACKGROUND

Hypertension is a prevalent cardiovascular disorder involving endothelial cell dysfunction. ITLN1 (Intelectin-1) is a fat-derived secreted adipokine that has been shown to enhance endothelium-dependent vasodilation through molecular signaling pathways that remain unclear.

METHODS

First, we generated endothelial-specific ITLN1 knockout (ITLN1EC-/-) mice to evaluate the functional consequences of ITLN1 deficiency on vascular homeostasis. Subsequently, experiments combining RNA sequencing, quantitative real-time PCR, immunoblotting, immunofluorescence, and nitric oxide quantification were used to elucidate the underlying signaling pathways involved. Finally, virtual molecular docking was used to identify puerarin 6-O-xyloside as a selective ITLN1-binding compound.

RESULTS

Hypertensive mice presented reduced ITLN1 abundance and decreased endothelial ITLN1 mRNA levels. Further studies revealed that ITLN1 overexpression via adenoviral vectors improved vascular relaxation in hypertensive models. Mechanistically, ITLN1 restored endothelial nitric oxide synthase phosphorylation by suppressing Wnt5b-JNK (c-jun N-terminal kinase) signaling, thereby increasing nitric oxide production. We subsequently elucidated ITLN1-modulating molecules and found that puerarin 6-O-xyloside upregulated ITLN1 expression and augmented vasodilation. Finally, ZNF460 was identified as a transcriptional repressor of ITLN1 in endothelial cells.

CONCLUSIONS

This study identified ITLN1 as a potential therapeutic target for hypertension. Upregulating ITLN1 protected against endothelial dysfunction by modulating Wnt5b-JNK/endothelial nitric oxide synthase signaling, with puerarin 6-O-xyloside serving as a promising ITLN1 activator.