Abstract Body: Background
Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide and is characterized by robust inflammatory responses that contribute to ischemic myocardial injury and adverse cardiac remodeling. Despite advances in therapeutic strategies, MI remains a leading risk factor for heart failure, highlighting the importance of elucidating immune mechanisms that regulate cardiac repair. Proprotein convertase subtilisin/kexin type 7 (PCSK7) is broadly expressed in cardiovascular and immune cells and has been implicated in cardiovascular disease. However, its role in regulating immune responses in the infarcted heart remains largely unknown. Here, we investigated the role of PCSK7 in post-MI immune regulation and cardiac remodeling.
Hypothesis
PCSK7 deficiency promotes reparative IL-4⁺ T cell responses, thereby reducing post-MI inflammation and adverse cardiac remodeling.
Aims
To investigate the role of PCSK7 in regulating cardiac T cell responses and IL-4–mediated immune remodeling after MI.
Methods
MI was induced in Pcsk7^+/+ and Pcsk7^−/− mice by permanent surgical occlusion of the left anterior descending (LAD) coronary artery. Cardiac function was assessed by echocardiography. An IL-4–neutralizing antibody was administered intraperitoneally after MI. Flow cytometry was performed to analyze cardiac immune cell populations, with a focus on T cell subsets. Quantitative PCR was used to evaluate the expression of genes associated with cardiac remodeling and inflammation during the post-MI recovery period and to explore signaling pathways involved in the inflammatory response.
Results
Loss of PCSK7 altered cardiac T cell composition, notably increasing reparative T cell populations. In the ischemic myocardium, IL-4⁺ T cells were significantly increased in Pcsk7^−/− mice. PCSK7 deficiency also reduced infarct size, attenuated cardiomyocyte apoptosis, and improved cardiac function after MI. Importantly, IL-4 neutralization abolished these protective effects, confirming that PCSK7 influences MI outcomes through IL-4–mediated immune responses. These findings indicate that PCSK7 deficiency promotes a reparative immune environment following MI.
Conclusions
PCSK7 plays a multifaceted role in cardiovascular disease by regulating reparative immune responses after MI. Targeting PCSK7 enhances IL-4⁺ T cell–mediated immune responses, thereby suppressing post-MI inflammation and mitigating disease severity.