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Hydrogen Sulfide Ameliorates Heart Aging by Downregulating Matrix Metalloproteinase-9

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Abstract

Purpose

Aging contributes significantly to cardiovascular diseases and cardiac dysfunction, leading to the upregulation of matrix metalloproteinase-9 (MMP-9) in the heart and a significant decrease in hydrogen sulfide (H2S) content, coupled with impaired cardiac diastolic function. This study explores whether supplementing exogenous hydrogen sulfide during aging ameliorates the decline in H2S concentration in the heart, suppresses MMP-9 expression, and improves the age-associated impairment in cardiac morphology and function.

Methods

We collected plasma from healthy individuals of different ages to determine the relationship between aging and H2S and MMP-9 levels through Elisa detection and liquid chromatography-tandem mass spectrometry (LC/MC) detection of plasma H2S content. Three-month-old mice were selected as the young group, while 18-month-old mice were selected as the old group, and sodium hydrosulfide (NaHS) was injected intraperitoneally from 15 months old until 18 months old as the old + NaHS group. Plasma MMP-9 content was detected using Elisa, plasma H2S content, cardiac H2S content, and cystathionine gamma-lyase (CSE) activity were detected using LC/MC, and cardiac function was detected using echocardiography. Heart structure was assessed using hematoxylin and eosin staining, Masone staining was used to detect the degree of cardiac fibrosis, while western blot was used to detect the expression of MMP-9, CSE, and aging marker proteins. Knockdown of MMP-9 and CSE in H9c2 cells using small interfering RNA was carried out to determine the upstream–downstream relationship between MMP-9 and CSE.

Results

H2S content in the plasma of healthy individuals decreases with escalating age, whereas MMP-9 level rises with age progression. Aging leads to a decrease in H2S levels in the heart and plasma of mice, severe impairment of cardiac diastolic function, interstitial relaxation, and fibrosis of the heart. Supplementing with exogenous H2S can improve these phenomena.

Conclusion

H2S maintains the structure and function of the heart by inhibiting the expression of MMP-9 during the aging process.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

The code that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (32271155, 91849120, and 31871154), the Natural Science Foundation of Hebei Province of China (C2020206025), and the University level Graduate Innovation Funding Project of Hebei Medical University in 2023 (XCXZZB202303).

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Authors and Affiliations

  1. Department of Physiology, Hebei Medical University, 050017, Hebei, China

    Kaichuan He, Chengqing Song, Danyang Tian, Lin **ao, Hongmei Xue, Qi Guo, Xu Teng, Sheng ** & Yuming Wu

  2. Core Facilities and Centers, Hebei Medical University, 050017, Hebei, China

    Huaxing Zhang

  3. Clinical Pharmacokinetic Laboratory, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China

    Bo Tan

  4. Clinical Practice Teaching Department, Hebei Medical University, 050017, Hebei, China

    Zihui Liang

  5. Department of Medical Laboratory, Hebei Children’s Hospital, 050017, Hebei, China

    Lixia Zhang

  6. Department of Psychiatry, the First Hospital of Hebei Medical University, 050031, Hebei, China

    Cuixia An

  7. Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, 050017, Hebei, China

    Yuming Wu

  8. Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, 050017, Hebei, China

    Yuming Wu

  9. The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 050017, Hebei, China

    Yuming Wu

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  1. Kaichuan He
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  2. Huaxing Zhang
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  3. Bo Tan
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  4. Chengqing Song
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  5. Zihui Liang
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  6. Lixia Zhang
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  7. Danyang Tian
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  8. Lin **ao
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  9. Hongmei Xue
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  10. Qi Guo
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  11. Xu Teng
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  12. Sheng **
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  13. Cuixia An
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  14. Yuming Wu
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Contributions

Conceptualization, CXA and YMW; methodology, KCH; software, HXZ; validation, BT, CQS, and ZHL; formal analysis, LXZ; investigation, DYT; resources, LX; data curation, HMX; writing—original draft preparation, QG; writing—review and editing, XT; visualization, SJ; supervision, YMW; project administration, CXA; funding acquisition, YMW All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Cuixia An or Yuming Wu.

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This study was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of Hebei Medical University, No.2018045.

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He, K., Zhang, H., Tan, B. et al. Hydrogen Sulfide Ameliorates Heart Aging by Downregulating Matrix Metalloproteinase-9. Cardiovasc Drugs Ther (2024). https://doi.org/10.1007/s10557-024-07586-w

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