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
Graphical Abstract
Keywords
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Article info
Publication history
Accepted:
January 5,
2023
Received in revised form:
January 5,
2023
Received:
September 7,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Brief Summary
Swietenine (Swi) exerts a preventive effect on vascular remodeling during pulmonary hypertension (PH) pathogenesis through enhancing mitophagy of pulmonary arterial smooth muscle cells (PASMCs), which is related to the reversion of the down-regulated Pink1 resulting from the translocation of Nrf2 into the nucleus induced by the interaction of Swi with Nrf2. Our findings reveal a novel role of Swi in alleviating the molecular pathogenesis of vascular remodeling in experimental PH, thereby revealing the therapeutic potential of Swi against PH.
Conflict of interest
All authors declare no conflict of interest.
Author information
Author Contributions
All authors contributed to the study. Conception, design and experiment: JD, CC and SL. Analysis and interpretation: PX, JW, LH, ZM, KL and YY. Drafting the manuscript for important intellectual content: WQ, FC and YY.
Consent for publication
Not applicable.
Availability of data and materials
Due to protection of patient data privacy, sharing of data on a publicly available repository is not possible, but data are available from the corresponding authors upon request.
Identification
Copyright
© 2023 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.
