Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3–MAPK Signaling to Trigger Spontaneous Aortic Dissection

作者：Tingting Zhang, Qingqing Lei, Jie He, Xin Guan, Xin Zhang, Ying Huang, Zi-Yue Zhou, Ruixin Fan, Ting Wang, Chenxi Li, Jin‐Yan Shang, Zhuomiao Lin, Wan-Li Peng, Li-Kai Xia, HE Yu-ling, Chuan-Ying Hong, Jing‐Song Ou, Rui‐Ping Pang, Xiaoping Fan, Hui Huang, Jia‐Guo Zhou · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.122.063029 · 被引用次数：44 · 研究领域：Nuclear Receptors and Signaling、NF-κB Signaling Pathways、Nerve injury and regeneration

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell–specific and endothelial cell–specific Best3 knockout mice (Best3 SMKO and Best3 ECKO , respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3 SMKO but not Best3 ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of M...