MAP2K2 Knockdown Suppresses Phenotypic Transformation of Vascular Smooth Muscle Cells in Aortic Dissection by Inactivating the JAK / STAT Signaling Pathway

ABSTRACT Aortic dissection (AD) is a severe aortic disease characterized by high morbidity and mortality. However, the primary treatments for AD possess limited efficacy. The role and specific mechanisms of mitogen‐activated protein kinase kinase 2 (MAP2K2) in AD are not elucidated. Human aortic vascular smooth muscle cells (HAVSMCs) induced by platelet‐derived growth factor‐BB (PDGF‐BB) and C57BL/6 mice treated with β‐aminopropionitrile were used as AD models in vitro and in vivo, respectively. RNA‐sequencing analysis was conducted to explore the downstream pathway of MAP2K2. The expression of tumor necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β), IL‐8, malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) was determined by enzyme‐linked immunosorbent assay. The protein levels of MAP2K2, alpha‐smooth muscle actin (α‐SMA), smooth muscle protein 22‐alpha (SM22α), Janus kinase 2 (JAK2), p‐JAK2, signal transducer and activator of the transcription 3 (STAT3), and p‐STAT3 were detected by western blot. We found that MAP2K2 was abnormally increased in AD. MAP2K2 knockdown repressed the expression levels of TNF‐α, IL‐1β, IL‐8, MDA, ROS, α‐SMA, and SM22α, and promoted SOD expression in vitro and in vivo. In addition, the JAK/STAT signaling pathway was identified as the downstream pathway of MAP2K2. MAP2K2 knockdown inhibited the expression of p‐JAK2/JAK2 and p‐STAT3/STAT3. Activating the JAK/STAT pathway by its activator RO8191 reversed the effect of MAP2K2 knockdown on inflammation, oxidative stress, and abnormal phenotypic transformation in HAVSMCs induced by PDGF‐BB. In conclusion, MAP2K2 knockdown could alleviate AD by inhibiting the JAK/STAT signaling pathway to repress inflammation, oxidative stress, and abnormal phenotypic transformation of HAVSMCs.