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 disease (CVD) pathogenesis.
• The role of post-translational SUMOylation in regulating SRF activity within the context of CVD remains largely unexplored.

Purpose of the Study:

• To investigate the impact of Senp1 deficiency on SRF SUMOylation and its downstream effects on VSMC phenotype and vascular remodeling.
• To elucidate the molecular mechanisms by which SRF SUMOylation influences the SRF-myocardin and SRF-ELK1 complexes in cardiovascular disease.

Main Methods:

• Utilized a mouse model with Senp1 deficiency in VSMCs to study vascular remodeling and neointimal formation.
• Analyzed SRF SUMOylation at lysine 143, SRF localization (lysosomal and nuclear), and SRF complex formation (SRF-myocardin vs. SRF-ELK1).
• Examined VSMCs from human coronary arteries of CVD patients for SUMOylated SRF and phospho-ELK1 levels.
• Assessed the therapeutic potential of the ELK inhibitor AZD6244 in a mouse model.

Main Results:

• Senp1 deficiency in VSMCs led to increased SRF SUMOylation and the SRF-ELK complex, augmenting vascular remodeling and neointimal formation.
• Mechanistically, increased SRF SUMOylation at K143 reduced lysosomal localization, increased nuclear accumulation, and shifted the SRF complex from myocardin to ELK1.
• Elevated SUMOylated SRF and phospho-ELK1 were observed in VSMCs from human CVD patients' coronary arteries.
• Inhibition of ELK with AZD6244 attenuated the SRF-myocardin to SRF-ELK complex shift, reducing VSMC synthetic phenotypes and neointimal formation in Senp1-deficient mice.

Conclusions:

• SRF SUMOylation, particularly under conditions of Senp1 deficiency, promotes a synthetic VSMC phenotype and contributes to cardiovascular disease progression.
• The SRF-ELK1 complex represents a key mediator in this process, and its inhibition shows therapeutic promise.
• Targeting the SRF complex, specifically the SRF-ELK interaction, offers a potential therapeutic avenue for treating cardiovascular diseases.