TWEAK Receptor Promotes Vascular Remodeling in Hypertension by Activating Autophagy

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Cellular Biology

Background:

• Vascular remodeling is a key factor in hypertensive target-organ damage, with autophagy playing a critical regulatory role.
• Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TWEAK receptor (TWEAKR) signaling is increasingly implicated in cardiovascular diseases.

Purpose of the Study:

• To investigate the relationship between TWEAK/TWEAKR signaling and autophagy in the context of hypertension-associated vascular remodeling.
• To elucidate the molecular mechanisms by which TWEAKR influences vascular smooth muscle cell behavior and autophagy.

Main Methods:

• Measured TWEAK levels and TWEAKR expression in hypertensive patients and spontaneously hypertensive rats.
• Utilized lentivirus-mediated TWEAKR knockdown in vitro and in vivo models.
• Employed a multi-omics approach including western blot, RT-PCR, co-IP, LC-MS, RNA-seq, and microscopy.

Main Results:

• TWEAKR expression was elevated in hypertension, while TWEAK levels remained unchanged.
• TWEAKR knockdown attenuated vascular remodeling and suppressed abnormal autophagy, independent of blood pressure.
• TWEAKR regulates autophagy via the ERK1/2 pathway by inhibiting TRIM21, which affects eIF4A3 ubiquitination and nuclear translocation.

Conclusions:

• TWEAKR plays a significant role in hypertension-induced vascular remodeling by modulating autophagy through the TRIM21/eIF4A3 axis.
• Targeting TWEAKR presents a promising therapeutic avenue for managing hypertension-related vascular pathologies.