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Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells

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Abstract

Aortic valve stenosis (AS) is the most common valvular heart disease but there are currently no effective medical treatments that can delay disease progression due to a lack of knowledge of the precise pathophysiology. The expression of sulfide: quinone oxidoreductase (SQOR) and nuclear factor erythroid 2-related factor 2 (NRF2) was decreased in the aortic valve of AS patients. However, the role of SQOR and NRF2 in the pathophysiology of AS has not been found. We investigated the effects of hydrogen sulfide (H2S)-releasing compounds on diseased aortic valve interstitial cells (AVICs) to explain the cellular mechanism of SQOR and elucidate the medical value of H2S for AS treatment. Sodium hydrosulfide (NaHS) treatment increased the expression of SQOR and NRF2 gene and consequently induced the NRF2 target genes, such as NAD(P)H quinone dehydrogenase 1 and cystathionine γ-lyase. In addition, NaHS dose-dependently decreased the expression level of fibrosis and inflammation-related genes (MMP9, TNF-α, IL6) and calcification-related genes (ALP, osteocalcin, RUNX2, COL1A1) in human AVICs. Furthermore, NaHS activated the AMPK-mTOR pathway and inhibited the PI3K-AKT pathway, resulting in a pro-autophagy effect in human AVICs. An NRF2 inhibitor, brusatol, attenuated NaHS-induced AMPK activation and decreased the autophagy markers Beclin-1 and LC3AB, suggesting that the mechanism of action of H2S is related to NRF2. In conclusion, H2S decreased gene expression levels related to aortic valve degeneration and activated AMPK-mTOR-mediated pro-autophagy function associated with NRF2 in human AVICs. Therefore, H2S could be a potential therapeutic target for the development of AS treatment.

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Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1I1A2A01060702). It was also supported by a grant (2022IF-0004) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

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Authors and Affiliations

  1. Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Naaleum Song, Jeong Eun Yu, Eunhye Ji, Kyoung-Hee Choi & Sahmin Lee

  2. Department of Medical Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, 88 Olympic-ro 43 Gil, Songpa-gu, Seoul, 05505, Republic of Korea

    Naaleum Song, Jeong Eun Yu & Sahmin Lee

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  1. Naaleum Song
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Contributions

SL contributed to the study conception and design as a corresponding author. Material preparation was performed by NS, JEY, EJ, KHC. Data collection and analysis were performed by NS. The first draft of the manuscript was written by NS and SL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sahmin Lee.

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The authors declare no competing interests.

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The study was performed in accordance with the ethical standards laid down in 1964 Declaration of Helsinki and its later amendments, and the Institutional Review Board (IRB) of Asan Medical Center (Seoul, Korea) approved the study protocol for the collection of human samples (IRB No. 2017 − 0556) and all patients gave their informed consent prior to their inclusion in the study.

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Song, N., Yu, J.E., Ji, E. et al. Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04881-2

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