Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling

作者：Saiyang Xie, Mengya Chen, Wenxi Fang, Shiqiang Liu, Qingqing Wu, Chen Liu, Yun Xing, Wenke Shi, Man Xu, Min Zhang, Si Chen, Xiaofeng Zeng, Shasha Wang, Wei Deng, Qizhu Tang · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104359 · 被引用次数：38 · 研究领域：Cardiac Fibrosis and Remodeling、Asthma and respiratory diseases、Cardiac electrophysiology and arrhythmias

BACKGROUND: Arachidonate 5-lipoxygenase (Alox5) belongs to a class of nonheme iron-containing dioxygenases involved in the catalysis of leukotriene biosynthesis. However, the effects of Alox5 itself on pathological cardiac remodeling and heart failure remain elusive. METHODS: The role of Alox5 in pathological cardiac remodeling was investigated by Alox5 genetic depletion, AAV9-mediated overexpression in cardiomyocytes, and a bone marrow (BM) transplantation approach. Neonatal rat cardiomyocytes were used to explore the effects of Alox5 in vitro. Molecular and signaling pathways were revealed by CUT &Tag, IP-MS, RNA sequencing and bioinformatic analyses. FINDINGS: Untargeted metabolomics showed that serum 5-HETE (a primary product of Alox5) levels were little changed in patients with cardiac hypertrophy, while Alox5 expression was significantly upregulated in murine hypertensive cardiac samples and human cardiac samples of hypertrophy, which prompted us to test whether high Alox5 levels under hypertensive stimuli were directly associated with pathologic myocardium in an enzymatic activity-independent manner. Herein, we revealed that Alox5 deficiency significantly ameliorated transverse aortic constriction (TAC)-induced hypertrophy. Cardiomyocyte-specific Alox5 depletion attenuated hypertensive ventricular remodeling. Conversely, cardiac-specifical Alox5 overexpression showed a pro-hypertrophic cardiac phenotype. Ablation of Alox5 in bone marrow-derived cells did not affect pat...