Abstract
Abstract
Background
Programmed cell death (PCD) has recently been implicated in modulating the removal of neutrophils recruited in acute myocardial infarction (AMI). Nonetheless, the clinical significance and biological mechanism of neutrophil-related PCD remain unexplored.
Methods
We employed an integrative machine learning-based computational framework to generate a predictive neutrophil-derived PCD signature (NPCDS) within five independent microarray cohorts from the peripheral blood of AMI patients. Non-negative matrix factorization was leveraged to develop an NPCDS-based AMI subtype. To elucidate the biological mechanism underlying NPCDS, we implemented single-cell transcriptomics on Cd45+ cells isolated from the murine heart of experimental AMI. We finally conducted a Mendelian randomization (MR) study and molecular docking to investigate the therapeutic value of NPCDS on AMI.
Results
We reported the robust and superior performance of NPCDS in AMI prediction, which contributed to an optimal combination of random forest and stepwise regression fitted on nine neutrophil-related PCD genes (MDM2, PTK2B, MYH9, IVNS1ABP, MAPK14, GNS, MYD88, TLR2, CFLAR). Two divergent NPCDS-based subtypes of AMI were revealed, in which subtype 1 was characterized as inflammation-activated with more vibrant neutrophil activities, whereas subtype 2 demonstrated the opposite. Mechanically, we unveiled the expression dynamics of NPCDS to regulate neutrophil transformation from a pro-inflammatory phase to an anti-inflammatory phase in AMI. We uncovered a significant causal association between genetic predisposition towards MDM2 expression and the risk of AMI. We also found that lidoflazine, isotetrandrine, and cepharanthine could stably target MDM2.
Conclusion
Altogether, NPCDS offers significant implications for prediction, stratification, and therapeutic management for AMI.
Funder
National Natural Science Foundation of China
Chenguang Program from the Shanghai Education Committee
Shanghai Sailing Program of Science and Technology Commission of Shanghai Municipality
Publisher
Springer Science and Business Media LLC