SCAP Interacts with Trim27 to Promote Vascular Neointimal Hyperplasia by Regulating the Stability and Ubiquitination...

Pathological vascular remodeling and intimal hyperplasia after vascular injury are representative pathological processes in age-associated vascular diseases. Previous data from our laboratory have indicated that sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) contributes to physiological angiogenesis during embryonic development. However, the role of SCAP in neointima formation is not fully understood. Here, we aimed to explore the mechanisms of SCAP in the proliferation and migration of vascular smooth muscle cells (VSMCs) during neointima formation after injury. We utilized three types of transgenic (Tg) mice to demonstrate that SCAP participates in the regulation of injury-induced neointima formation in the vascular wall by promoting the proliferation and migration of VSMCs. This novel function of SCAP is associated with the activation of the NF-κB/MMP2/9 signaling pathway. Importantly, we reported for the first time that SCAP activates the NF-κB pathway by promoting Trim27-mediated ubiquitination of the IκBα protein and accelerating its degradation, consequently activating MMP2/9 transcription, which resulted in migration and proliferation of VSMCs. We thus propose that SCAP/IκBα/NF-κB axis is a novel signaling pathway involved in the regulation of neointimal hyperplasia, and targeting this axis may have implications for preventing neointimal hyperplasia-related diseases.