GPX3 Overexpression Ameliorates Cardiac Injury Post Myocardial Infarction Through Activating LSD1/Hif1α Axis

• Published in: Journal of cellular and molecular medicine Vol. 29; no. 3; pp. e70398 - n/a
• Main Authors: Jiang, Qi‐Qi, Du, Chong, Qian, Ling‐Ling, Shan, Tian‐Kai, Bao, Yu‐Lin, Gu, Ling‐Feng, Wang, Si‐Bo, Yang, Tong‐Tong, Zhou, Liu‐Hua, Wang, Ze‐Mu, He, Ye, Wang, Qi‐Ming, Wang, Hao, Wang, Ru‐Xing, Wang, Lian‐Sheng
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2025; John Wiley and Sons Inc
• Subjects: Adaptation; Adenoviruses; Animals; Apoptosis; Apoptosis - genetics; Cardiac arrhythmia; cardiomyocyte apoptosis; Cardiomyocytes; Congestive heart failure; Disease Models, Animal; Ejection fraction; Enzymes; Epigenetics; Glucose; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; GPX3; Heart attacks; Hif1α; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunofluorescence; Intubation; Ischemia; LSD1; Male; Mice; Mice, Inbred C57BL; Molecular modelling; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Original; Ostomy; oxidative stress; Reactive oxygen species; Reactive Oxygen Species - metabolism; Recovery of function; Signal Transduction; Survival; Therapeutic targets; United States > US; Hif1α; GPX3; cardiomyocyte apoptosis; oxidative stress; LSD1; myocardial infarction
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.70398

ABSTRACT Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM‐specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3‐related effects. Multi‐omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen–glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM‐specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long‐term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post‐MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment.