AUTHOR=Liang Jingjing , Cao Yue , He Mingli , Li Weiwen , Huang Guolin , Ma Tianyi , Li Meijun , Huang Yuli , Huang Xiaohui , Hu Yunzhao 

TITLE=AKR1C3 and Its Transcription Factor HOXB4 Are Promising Diagnostic Biomarkers for Acute Myocardial Infarction

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.694238

DOI=10.3389/fcvm.2021.694238

ISSN=2297-055X

ABSTRACT=Background: Recent study disclosed that ferroptosis was an important myocyte death style in myocardial infarction (MI). However, the diagnostic value of ferroptosis regulators and correlated underlying mechanisms in acute myocardial infarction (AMI) remain unknown. 
Methods: The bioinformatical analyses were conducted to identify the candidate biomarkers for AMI, and the collected local samples were used to validate the findings via real-time quantitative PCR (RT-qPCR). Bioinformatical analysis and luciferase reporter assay was implemented to identify the transcriptional factor. The transient transfection and ferroptosis characteristics measurement, including GPX4, MDA, iron, and GSH, were performed to verify the ability of the candidate gene to regulate ferroptosis of cardiomyocytes. Meta-analysis was conducted in multiple independent cohorts to clarify the diagnostic value. 
Results: 121 ferroptosis regulators were extracted from previous studies, and AKR1C3 was significantly down-regulated in peripheral blood samples of AMI cases from the analysis of GSE48060 and GSE97320. HOXB4 served as a transcriptional activator for AKR1C3, and could suppress the ferroptosis of the H9C2 cells treated with Erastin. Besides, peripheral blood samples from 16 AMI patients and 16 patients without coronary atherosclerotic disease were collected, where AKR1C3 and HOXB4 both showed high diagnostic ability. Furthermore, a nomogram including HOXB4 and AKR1C3 was established and successfully validated in 6 independent datasets. Clinical correlation analysis displayed AKR1C3 and HOXB4 were correlated with smoking, CK, CK-MB, and N-Terminal-pro-B-Type Natriuretic Peptide. 
Conclusion: Taken together, this study demonstrates that AKR1C3 and HOXB4 were promising diagnostic biomarkers, providing novel insights into the ferroptosis mechanisms of AMI.