SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling

Area of Science:

• Molecular biology
• Cardiovascular research
• Cellular signaling

Background:

• Serum response factor (SRF) regulates vascular smooth muscle cell (VSMC) phenotype, crucial in cardiovascular diseases (CVD).
• Post-translational modification, specifically SUMOylation, is implicated in SRF regulation, but its role in CVD remains unclear.

Approach:

• Investigated the impact of Senp1 deficiency on SRF SUMOylation and its consequences in VSMCs.
• Utilized mouse models and patient-derived cells to elucidate the mechanism of SRF SUMOylation in vascular remodeling.
• Examined the effect of targeting the SRF-ELK complex using AZD6244 in Senp1-deficient mice.

Key Points:

• Senp1 deficiency in VSMCs enhances SRF SUMOylation at lysine 143, increasing nuclear accumulation and promoting a shift from myocardin to phosphorylated ELK1 cofactors.
• This SRF-ELK complex formation drives VSMC proliferation, migration, and synthetic phenotype, exacerbating vascular remodeling and neointimal hyperplasia.
• Elevated SUMOylated SRF and phosphor-ELK1 were observed in VSMCs from CVD patients' coronary arteries.

Conclusions:

• Senp1-mediated regulation of SRF SUMOylation is critical for maintaining VSMC homeostasis and preventing pathological vascular remodeling.
• The SRF-ELK complex is a key driver of CVD pathogenesis, representing a potential therapeutic target.
• Targeting the SRF complex, specifically the SRF-ELK interaction, may offer a novel strategy for treating cardiovascular diseases.