YB-1 Recruits Drosha to Promote Splicing of <i>pri-miR-192</i> to Mediate the Proangiogenic Effects of H <sub>2</sub> S
Yu Zhou, Xinghui Li, Wenlong Xue, Sheng Jin, Mengyao Li, Caicai Zhang, Bo Yu, Lei Zhu, Kun Liang, Ying Chen, Bei‐Bei Tao, Yi Zhun Zhu, Yi-Zhun Zhu, Ming-Jie Wang, Yi‐Chun Zhu, Yi‐Chun Zhu
Abstract
Aims: The genes targeted by miRNAs have been well studied. However, little is known about the feedback mechanisms to control the biosynthesis of miRNAs that are essential for the miRNA feedback networks in the cells. In this present study, we aimed at examining how hydrogen sulfide (H 2 S) promotes angiogenesis by regulating miR-192 biosynthesis. Results: H 2 S promoted in vitro angiogenesis and angiogenesis in Matrigel plugs embedded in mice by upregulating miR-192 . Knockdown of the H 2 S-generating enzyme cystathionine γ-lyase (CSE) suppressed in vitro angiogenesis, and this suppression was rescued by exogenous H 2 S donor NaHS. Plakophilin 4 ( PKP4 ) served as a target gene of miR-192 . H 2 S up-regulated miR-192 via the VEGFR2/Akt pathway to promote the splicing of primary miR-192 ( pri-miR-192 ), and it resulted in an increase in both the precursor- and mature forms of miR-192 . H 2 S translocated YB-1 into the nuclei to recruit Drosha to bind with pri-miR-192 and promoted its splicing. NaHS treatment promoted angiogenesis in the hindlimb ischemia mouse model and the skin-wound-healing model in diabetic mice, with upregulated miR-192 and downregulated PKP4 on NaHS treatment. In human atherosclerotic plaques, miR-192 levels were positively correlated with the plasma H 2 S concentrations. Innovation and Conclusion: Our data reveal a role of YB-1 in recruiting Drosha to splice pri-miR-192 to mediate the proangiogenic effect of H 2 S. CSE/H 2 S/YB-1/Drosha/ miR-192 is a potential therapeutic target pathway for treating diseases, including organ ischemia and diabetic complications. Antioxid. Redox Signal . 36, 760–783. The Clinical Trial Registration number is 2016–224.