TaoHe ChengQi decoction ameliorates sepsis-induced cardiac dysfunction through anti-ferroptosis via the Nrf2 pathway

Si-Min Lu; Bo Yang; Zhang-Bin Tan; Hui-Juan Wang; Jun-di Xie; Meng-Ting Xie; Wei-Hao Jiang; Jin-Zhou Huang; Jun Li; Lei Zhang; Yong-Zhen Tan; Jing-Zhi Zhang; Bin Liu; Wei-Wei Wu; Shuang-Wei Zhang

doi:10.1016/j.phymed.2024.155597

TaoHe ChengQi decoction ameliorates sepsis-induced cardiac dysfunction through anti-ferroptosis via the Nrf2 pathway

Phytomedicine. 2024 Apr 20:129:155597. doi: 10.1016/j.phymed.2024.155597. Online ahead of print.

Authors

Si-Min Lu¹, Bo Yang¹, Zhang-Bin Tan¹, Hui-Juan Wang¹, Jun-di Xie¹, Meng-Ting Xie¹, Wei-Hao Jiang¹, Jin-Zhou Huang², Jun Li³, Lei Zhang⁴, Yong-Zhen Tan¹, Jing-Zhi Zhang¹, Bin Liu⁵, Wei-Wei Wu⁶, Shuang-Wei Zhang⁷

Affiliations

¹ Department of Traditional Chinese Medicine, Guangzhou Institute of Cardiovascular Disease, State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou 510260, China.
² Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
³ School of Pharmacy, Inner Mongolia Medical University, Hohhot 010000,China.
⁴ Henan University of Chinese Medicine, Zhengzhou 82004112, China.
⁵ Department of Traditional Chinese Medicine, Guangzhou Institute of Cardiovascular Disease, State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou 510260, China. Electronic address: xmhoolv@163.com.
⁶ Department of Rehabilitation, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Electronic address: gyeywu@126.com.
⁷ Department of Traditional Chinese Medicine, Guangzhou Institute of Cardiovascular Disease, State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou 510260, China. Electronic address: zhangsw0315@163.com.

PMID: 38643713
DOI: 10.1016/j.phymed.2024.155597

Abstract

Background: Sepsis-induced cardiac dysfunction (SICD) is a serious complication of sepsis that is associated with increased mortality. Ferroptosis has been reported in the SICD. TaoHe ChengQi decoction (THCQD), a classical traditional Chinese medicinal formula, has multiple beneficial pharmacological effects. The potential effects of THCQD on the SICD remain unknown.

Purpose: To investigate the effect of THCQD on SICD and explore whether this effect is related to the regulation of myocardial ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2) activation.

Methods: We induced sepsis in a mouse model using cecal ligation and puncture (CLP) and administered THCQD (2 and 4 g/kg) and dexamethasone (40 mg/kg). Mice mortality was recorded and survival curves were plotted. Echocardiography, hematoxylin and eosin staining, and analysis of serum myocardial injury markers and inflammatory factors were used to evaluate cardiac pathology. Myocardial ferroptosis was detected by quantifying specific biomarker content and protein levels. Through HPLC-Q-Exactive-MS analysis, we identified the components of the THCQD. Network pharmacology analysis and Cellular Thermal Shift Assay (CETSA) were utilized to predict the targets of THCQD for treating SICD. We detected the expression of Nrf2 using Western blotting or immunofluorescence. An RSL3-induced ferroptosis model was established using neonatal rat cardiomyocytes (NRCMs) to further explore the pharmacological mechanism of THCQD. In addition to measuring cell viability, we observed changes in NRCM mitochondria using electron microscopy and JC-1 staining. NRF2 inhibitor ML385 and Nrf2 knockout mice were used to validate whether THCQD exerted protective effects against SICD through Nrf2-mediated ferroptosis signaling.

Results: THCQD reduced mortality in septic mice, protected against CLP-induced myocardial injury, decreased systemic inflammatory response, and prevented myocardial ferroptosis. Network pharmacology analysis and CETSA experiments predicted that THCQD may protect against SICD by activating the Nrf2 signaling pathway. Western blotting and immunofluorescence showed that THCQD activated Nrf2 in cardiac tissue. THCQDs consistently mitigated RSL3-induced ferroptosis in NRCM, which is related to Nrf2. Furthermore, the pharmacological inhibition of Nrf2 and genetic Nrf2 knockout partially reversed the protective effects of THCQD on SICD and ferroptosis.

Conclusion: The effect of THCQD on SICD was achieved by activating Nrf2 and its downstream pathways.

Keywords: Cardiac dysfunction; Cardiomyocyte; Ferroptosis; Nrf2; Sepsis; THCQD.