SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling

• Published in: Nature communications Vol. 15; no. 1; pp. 6919 - 18
• Main Authors: Xu, Yue, Zhang, Haifeng, Chen, Yuxin, Pober, Jordan S., Zhou, Min, Zhou, Jenny Huanjiao, Min, Wang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-08-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/95; 14/1; 14/19; 14/63; 38/22; 38/23; 631/80/304; 64/110; 692/308/1426; 692/4019/592/75/593/1301; 96; Animals; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Coronary artery; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Genotype & phenotype; Heart diseases; Humanities and Social Sciences; Humans; Localization; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Muscle contraction; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; Neointima - metabolism; Neointima - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathogenesis; Phenotype; Phenotypes; Post-translation; Science; Science (multidisciplinary); Serum response factor; Serum Response Factor - genetics; Serum Response Factor - metabolism; Smooth muscle; SUMO protein; Sumoylation; Trans-Activators - genetics; Trans-Activators - metabolism; Translation; Vascular Remodeling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51350-5

Serum response factor (SRF) controls gene transcription in vascular smooth muscle cells (VSMCs) and regulates VSMC phenotypic switch from a contractile to a synthetic state, which plays a key role in the pathogenesis of cardiovascular diseases (CVD). It is not known how post-translational SUMOylation regulates the SRF activity in CVD. Here we show that
Senp1
deficiency in VSMCs increased SUMOylated SRF and the SRF-ELK complex, leading to augmented vascular remodeling and neointimal formation in mice. Mechanistically, SENP1 deficiency in VSMCs increases SRF SUMOylation at lysine 143, reducing SRF lysosomal localization concomitant with increased nuclear accumulation and switching a contractile phenotype-responsive SRF-myocardin complex to a synthetic phenotype-responsive SRF-ELK1 complex. SUMOylated SRF and phospho-ELK1 are increased in VSMCs from coronary arteries of CVD patients. Importantly, ELK inhibitor AZD6244 prevents the shift from SRF-myocardin to SRF-ELK complex, attenuating VSMC synthetic phenotypes and neointimal formation in
Senp
1-deficient mice. Therefore, targeting the SRF complex may have a therapeutic potential for the treatment of CVD.
How post-translational SUMOylation regulates the SRF activity in cardiovascular disease is unclear. Here, the authors report that SRF SUMOylation increased by SENP1 deficiency switches vascular smooth muscle cells from a healthy contractile phenotype to a disease-associated synthetic phenotype.