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.