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SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling

Yue Xu1,2, Haifeng Zhang1, Yuxin Chen3

  • 1Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Nature Communications
|August 12, 2024
PubMed

Insights

Senp1 deficiency in vascular smooth muscle cells (VSMCs) increases SUMOylated SRF, promoting cardiovascular disease. Targeting the SRF-ELK complex may offer new therapeutic strategies for treating cardiovascular diseases (CVD).

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.

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