2. Academic Validation
  3. Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling

Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling

  • Free Radic Biol Med. 2022 Mar;181:130-142. doi: 10.1016/j.freeradbiomed.2022.01.020.
Zhenzhou Zhang 1,  Jianqiong Tang 2,  Jiawei Song 1,  Mengshi Xie 3,  Ying Liu 1,  Zhaojie Dong 4,  Xiaoyan Liu 4,  Xueting Li 5,  Miwen Zhang 5,  Yihang Chen 5,  Hongyu Shi 6,  Jiuchang Zhong 7
Affiliations

Affiliations

  • 1 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 2 Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
  • 3 Department of Cardiology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
  • 4 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 5 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 6 Department of Cardiology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China. Electronic address: shi-hy@hotmail.com.
  • 7 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China; Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. Electronic address: jczhong@sina.com.
PMID: 35122997 DOI: 10.1016/j.freeradbiomed.2022.01.020
Abstract

Hypertension-mediated pathological cardiac remodeling often progresses to heart failure. Elabela, mainly expressed in the cardiac microvascular endothelial cells (CMVECs), functions as a new endogenous ligand for apelin receptor. However, the exact roles of elabela in hypertension remain largely unclear. In this study, 10-week-old male C57BL/6 mice were randomly subjected to infusion of angiotensin (Ang) II (1.5 mg/kg/d) or saline for 2 weeks. Ang II infusion led to marked increases in systolic blood pressure levels and reduction of elabela levels in hypertensive mice with augmented myocardial hypertrophy and fibrosis. Furthermore, administration of elabela or Ferroptosis inhibitor ferrostatin-1 significantly prevented Ang II-mediated pathological myocardial remodeling, dysfunction, and ultrastructural injury in hypertensive mice with downregulated expression of inflammation-, hypertrophy-, and fibrosis-related genes. Notably, elabela strikingly alleviated Ang II-induced upregulation of iron levels and lipid peroxidation in hypertensive mice by suppressing cardiac interleukin-6 (IL-6)/STAT3 signaling and activating the xCT/Glutathione Peroxidase (GPX4) signaling. In cultured CMVECs, exposure to Ang II resulted in a marked decrease in elabela levels and obvious increases in cellular Ferroptosis, proliferation, inflammation, and superoxide production, which were rescued by elabela or ferrostatin-1 while were blocked by co-treatment with rhIL-6. Furthermore, knockdown of elabela by siRNA in CMVECs contributed to Ang II-mediated augmentations in cellular proliferation, migration, and oxidative stress in cultured cardiac fibroblasts and cardiomyocytes, respectively. In conclusion, elabela antagonizes Ang II-mediated promotion of CMVECs Ferroptosis, adverse myocardial remodeling, fibrosis and heart dysfunction through modulating the IL-6/STAT3/GPX4 signaling pathway. Targeting elabela-APJ axis serves as a novel strategy for hypertensive heart diseases.

Keywords

Cardiac microvascular endothelial cells; Elabela; Ferroptosis; Hypertension; Myocardial remodeling.

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