Time-series analysis of gene expression identifies of FKBP4 as a novel protective factor in severe acute pancreatitis-associated myocardial injury.

Abstract

Acute pancreatitis (AP), a prevalent inflammatory condition, can result in systemic complications, including myocardial injury. Nevertheless, the dynamic transcriptomic alterations and key molecular mechanisms underlying pancreatic-associated cardiac complications during AP progression are still not fully elucidated. Male Sprague-Dawley (SD) rats (8-10 weeks old) were subjected to retrograde infusion of 5% sodium taurocholate into the pancreatic and biliary ducts to induce severe acute pancreatitis (SAP). Myocardial injury was evaluated through echocardiographic assessment, measurement of serum cardiac enzyme levels, and histopathological examination. Temporal gene expression profiles in cardiac tissues were analyzed using microarray technology. A total of 1824 differentially expressed genes (DEGs) were identified in cardiac tissues at 12, and 24 h post-SAP induction compared to Sham controls. These DEGs were predominantly associated with ischemia, hypoxia, apoptosis, mitochondrial fission, and oxidative stress in cardiac tissues following the induction of SAP. Co-expression network analysis revealed that FKBP4, a member of the immunophilin protein family involved in steroid receptor signaling and protein folding, was centrally positioned within the gene network. FKBP4 expression was significantly downregulated in cardiac tissues at all time points following SAP induction. Cardiomyocyte-specific overexpression of FKBP4 markedly attenuated myocardial injury, reduced inflammatory infiltration and oxidative stress, and decreased mitochondrial fission and cardiomyocyte apoptosis. Mechanistically, FKBP4 overexpression upregulated HSP90 and SERCA2 expression, suppressed the activation of Drp1 and p-P65, and ultimately improved cardiac contractile function. These findings suggest that FKBP4 represents a candidate molecule that warrants further mechanistic and preclinical investigation in the context of pancreatitis-associated myocardial injury.