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Canadian Journal of Cardiology

Swietenine Alleviates Vascular Remodeling by Enhancing Mitophagy of Pulmonary Arterial Smooth Muscle Cells in Experimental Pulmonary Hypertension

Published:January 11, 2023DOI:https://doi.org/10.1016/j.cjca.2023.01.003

      Abstract

      Background

      Vascular remodeling during pulmonary hypertension (PH) is characterized by the phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs). Swietenine (Swi), extracted from the seeds of traditional medicine Swietenia mahagoni, has been used to treat cardiac remodeling, but the effect of Swi on PH is unknown. This study aims to evaluate the effect of Swi on hypoxia-induced phenotypic transformation of PASMCs in experimental PH.

      Methods

      In our research, C57BL/6 mice were treated with SU5416 and exposed to hypoxia for 4 weeks to establish HySu-PH model. Mice in Swi treatment group were subjected to HySu with daily administration of Swi. Hemodynamic parameters, echocardiography, and degree of vascular muscularization were measured to evaluate PH model. PASMCs proliferation was assessed by Ki67 and EdU assay. Cell migration was detected by wound healing assay. Mitophagy levels were evaluated by mito-tracker and lyso-tracker, autophagic flux, and protein expression of Pink1 and Lc3Ⅱ. The molecular docking was used to validate the interaction of Swi with Nrf2. Immunofluorescence and immunohistochemical staining were applied to determine the subcellular localization of Nrf2.

      Results

      The results showed that Swi attenuated hypoxia-induced increase of right ventricle systolic pressure, Fulton index, and vascular remodeling and decreased PASMCs proliferation, migration, and enhanced mitophagy. What’s more, the interaction of Swi with Nrf2 promoted the translocation of Nrf2 into the nucleus, resulting in the induction of Pink1.

      Conclusions

      This study demonstrates that Swi prevents vascular remodeling in experimental PH through inhibition of phenotypic transformation and hyperproliferation of PASMCs caused by reversing hypoxia-induced inhibition of mitophagy.

      Graphical abstract

      Keywords

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