1. CircLMBR1 inhibits phenotypic transformation of hypoxia-induced pulmonary artery smooth muscle via the splicing factor PUF60.
- Author
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Wang H, Gao Y, Bai J, Liu H, Li Y, Zhang J, Ma C, Zhao X, Zhang L, Wan K, and Zhu D
- Subjects
- Animals, Humans, Mice, RNA, Circular genetics, RNA, Circular metabolism, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Muscle, Smooth, Vascular drug effects, Male, Splicing Factor U2AF genetics, Splicing Factor U2AF metabolism, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary pathology, Hypertension, Pulmonary genetics, Hypoxia metabolism, Hypoxia genetics, Mice, Inbred C57BL, Cell Hypoxia, Indoles pharmacology, Pyrroles, Pulmonary Artery metabolism, Pulmonary Artery pathology, Pulmonary Artery drug effects, Vascular Remodeling drug effects, Vascular Remodeling genetics, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle pathology, Phenotype
- Abstract
Phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) contributes to vascular remodeling in hypoxic pulmonary hypertension (PH). Recent studies have suggested that circular RNAs (circRNAs) may play important roles in the vascular remodeling of hypoxia-induced PH. However, whether circRNAs cause pulmonary vascular remodeling by regulating the phenotypic transformation in PH has not been investigated. Microarray and RT-qPCR analysis identified that circLMBR1, a novel circRNA, decreased in mouse lung tissues of the hypoxia-SU5416 PH model, as well as in human PASMCs and mouse PASMCs exposed to hypoxia. Overexpression of circLMBR1 in the Semaxinib (SU5416) mouse model ameliorated hypoxia-induced PH and vascular remodeling in the lungs. Notably, circLMBR1 was mainly distributed in the nucleus and bound to the splicing factor PUF60. CircLMBR1 suppressed the phenotypic transformation of human PASMCs and vascular remodeling by inhibiting PUF60 expression. Furthermore, we identified U2AF65 as the downstream regulatory factor of PUF60. U2AF65 directly interacted with the pre-mRNA of the contractile phenotype marker smooth muscle protein 22-α (SM22α) and inhibited its splicing. Meanwhile, hypoxia exposure increased the formation of the PUF60-U2AF65 complex, thereby inhibiting SM22α production and inducing the transition of human PASMCs from a contractile phenotype to a synthetic phenotype. Overall, our results verified the important role of circLMBR1 in the pathological process of PH. We also proposed a new circLMBR1/PUF60-U2AF65/pre-SM22α pathway that could regulate the phenotypic transformation and proliferation of human PASMCs. This study may provide new perspectives for the diagnosis and treatment of PH., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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