Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

The study investigates the role of the deubiquitinase OTUB1 in vascular smooth muscle cells (VSMCs) within the context of atherosclerosis, a disease characterized by lipid accumulation and plaque formation in arteries. Atherosclerosis is a major cause of cardiovascular and cerebrovascular diseases, with VSMCs playing a significant role in its development. The research explores the potential of targeting OTUB1 to modulate the phenotype switch of VSMCs, which is considered a critical pathological process in atherosclerosis.

Ubiquitylation, a post-translational modification, has been implicated in the regulation of VSMC phenotype switch. Deubiquitinases, such as OTUB1, can remove ubiquitin chains from substrates, protecting proteins from degradation. The study hypothesizes that OTUB1 may influence the pathophysiology of VSMCs during atherosclerosis by modulating the stability of proteins like PDGFRβ, a key player in cell proliferation and migration.

To test this hypothesis, researchers constructed an atherosclerosis mouse model and used human aortic smooth muscle cells (HASMCs) to investigate the effects of OTUB1 depletion on phenotype changes and molecular mechanisms. The findings indicate that knocking down OTUB1 ameliorates plaque progression and stabilizes atherosclerotic plaques. Mechanistic insights reveal that OTUB1 increases the stability of PDGFRβ by removing K48-linked ubiquitylation, thus inhibiting the phenotype switch of VSMCs.

The study further demonstrates that OTUB1 is necessary for platelet-derived growth factor-BB (PDGF-BB)-induced proliferation, phenotype switching, and migration of HASMCs. RNA sequencing and mass spectrometry analysis identify a set of differentially expressed genes and proteins whose ubiquitylation is affected by OTUB1 depletion. These include proteins implicated in atherogenesis, such as PDGFRβ, which is found to interact with OTUB1 and is regulated by it through K48-linked ubiquitylation.

In vivo experiments in apolipoprotein E-deficient (Apoe−/−) mice show that silencing Otub1 reduces atherosclerotic plaque burden and enhances plaque stability, particularly in the advanced stages of atherosclerosis. The study suggests that by targeting OTUB1, it may be possible to develop novel therapeutic strategies for atherosclerosis and cardiovascular diseases.

The research acknowledges the complexity of atherosclerosis and the multifaceted role of VSMCs in its progression. It highlights the importance of understanding the molecular mechanisms underlying the phenotype switch of VSMCs and the potential of targeting deubiquitinases like OTUB1 for therapeutic intervention. The study's findings contribute to the growing body of evidence that supports the role of ubiquitin-proteasome system in the regulation of atherosclerosis and identify OTUB1 as a promising target for future research and drug development.

Overall, the study provides a comprehensive analysis of the role of OTUB1 in atherosclerosis, offering new insights into the molecular mechanisms that govern VSMC behavior and the potential for targeted therapies. The findings underscore the importance of early intervention and the modulation of key proteins like PDGFRβ to prevent or treat atherosclerosis effectively.