Korean J Physiol Pharmacol.  2023 Jan;27(1):1-8. 10.4196/kjpp.2023.27.1.1.

Hydrogen sulfide alleviates hypothyroidism-induced myocardial fibrosis in rats through stimulating autophagy and inhibiting TGF-β1/Smad2 pathway

• Song X
• Nie L
• Long J
• Zhao J
• Liu X
• Wang L
• Liu D
• Wang S
• Liu S
• Yang J

• KMID: 2537498
• DOI: http://doi.org/10.4196/kjpp.2023.27.1.1

Abstract

Hypothyroidism alone can lead to myocardial fibrosis and result in heart failure, but traditional hormone replacement therapy does not improve the fibrotic situation. Hydrogen sulfide (H ₂ S), a new gas signaling molecule, possesses antiinflammatory, antioxidant, and anti-fibrotic capabilities. Whether H ₂ S could improve hypothyroidism-induced myocardial fibrosis are not yet studied. In our study, H ₂ S could decrease collagen deposition in the myocardial tissue of rats caused by hypothyroidism. Furthermore, in hypothyroidism-induced rats, we found that H ₂ S could enhance cystathionine-gamma-lyase (CSE), not cystathionine β-synthase (CBS), protein expressions. Finally, we noticed that H ₂ S could elevate autophagy levels and inhibit the transforming growth factor-β1 (TGF-β1) signal transduction pathway. In conclusion, our experiments not only suggest that H ₂ S could alleviate hypothyroidism-induced myocardial fibrosis by activating autophagy and suppressing TGF-β1/ SMAD family member 2 (Smad 2) signal transduction pathway, but also show that it can be used as a complementary treatment to conventional hormone therapy.

Keyword

Autophagy; Fibrosis; Hydrogen sulfide (H ₂ S); Hypothyroidism; Transforming growth factor beta1

Figure

• 

  Fig. 1 Hydrogen sulfide (H2S) could ameliorate hypothyroidism-induced myocardial fibrosis and dysfunction. (A, B) Results of Masson staining in myocardial tissue among four groups. The red part represents the arrangement of myocardial tissue, and the blue part represents myocardial collagen deposition (A: magnification ×40). (C) Cardiac function was evaluated by M-mode echocardiography (a: Control group, b: PTU group, c: PTU+H2S group, d: H2S group). PTU, propylthiouracil. *p < 0.05 compared with Control group; #p < 0.05 compared with PTU group.

• 

  Fig. 2 Hydrogen sulfide (H2S) can enhance CSE protein expression and TIMP2/MMP13 protein expression ratio. (A–C) CSE and CBS protein expressions among four groups. (D, E) MMP13 and TIMP2 protein expressions among four groups. CSE, cystathionine-gamma-lyase; CBS, cystathionine β-synthase; MMP13, matrix metalloproteinase 13; TIMP2, tissue inhibitor of metalloproteinase 2; PTU, propylthiouracil. *p < 0.05 compared with Control group; #p < 0.05 compared with PTU group.

• 

  Fig. 3 Hydrogen sulfide (H2S) can inactivate the TGF-β1/Smad2 pathway activated by PTU and upregulate the autophagy downregulated by PTU. (A–C) TGF-β1 and Smad2, p-Smad2 protein expressions among four groups. (D–F) Atg4, Atg5, Beclin1, LC3II/I and P62 protein expressions among four groups. TGF-β1, transforming growth factor-β1; Smad2, SMAD family member 2; PTU, propylthiouracil. *p < 0.05 compared with Control group; #p < 0.05 compared with PTU group.

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