Epigenetic Modulation of Vascular Smooth Muscle Cell Phenotype Switching in Early-Onset Acute Myocardial Infarction.

BACKGROUND

The epigenetic mechanisms underlying early-onset acute myocardial infarction (AMI) remain insufficiently characterized. The present study aims to elucidate the pathophysiology of early-onset AMI by investigating its epigenetic features as molecular indicators.

METHODS

A comparative differential methylation analysis was performed on whole blood samples from 298 patients with early-onset AMI with clinical follow-up and 247 controls using targeted bisulfite sequencing. Clusters of differentially methylated sites (CDMSs) were defined to highlight regions of concentrated methylation changes in patients with early-onset AMI. Cox proportional hazards regression was conducted to evaluate the prognostic significance of the methylation biomarkers.

RESULTS

A total of 692 differentially methylated sites (DMSs) were identified as biomarkers associated with early-onset AMI. Among these, 396 DMSs were grouped into 147 CDMSs. Notably, the UHRF1 and STIMATE genes, which regulate synthetic and osteoblast-like vascular smooth muscle cell phenotypes, respectively, contained CDMSs with the highest number of significant DMSs. UHRF1 demonstrated a CDMS with 10 significant DMSs within a 117-bp region, while STIMATE included a 264-bp CDMS with 10 significant DMSs. Both regions also exhibited consistent methylation patterns in coronary tissues, comparing human coronary plaque to normal coronary artery samples. Additionally, the HIPK3 gene, which modulates STAT3 (signal transducer and activator of transcription 3) expression, thereby promoting osteoblast-like transformation in vascular smooth muscle cells, showed a CDMS with 5 significant DMSs within a 123-bp region, with further validation in the corresponding tissues. Furthermore, over 66% biomarkers demonstrated significant associations with mortality in patients with early-onset AMI, providing evidence of the impact of these biomarkers on the pathophysiology of the disease.

CONCLUSIONS

This innovative epigenomic study into early-onset AMI not only identifies biomarkers associated with the disease and its mortality but also highlights the critical role of vascular smooth muscle cell phenotype regulation in early-onset AMI pathogenesis. Our findings suggest that changes in vascular smooth muscle cell phenotypes toward synthetic and osteoblast-like states play a crucial role in early-onset AMI.