Asporin Improves Cardiac Myocyte Response to Ischemia and Reperfusion Stress.

Background: Myocardial Infarction (MI) remains a leading cause of mortality worldwide, despite advancements in clinical therapies and interventions. MI results from prolonged ischemia, leading to hypoxia-induced damage to cardiac tissue and reperfusion-injury (R/I) that aggravates cardiomyocyte (CM) loss. One key cellular event during this process is accumulation of dysfunctional mitochondria, resulting from environmental hypoxia and subsequent oxidative stress upon reperfusion. Post-MI cardiac-remodeling involves changes in both cellular and extracellular matrix (ECM). Ubiquitin-dependent and independent autophagy are crucial for cardio protection during this phase. The ECM provides structural integrity and functions as a reservoir for signaling molecules. Asporin (ASPN), a small leucine-rich proteoglycan, plays a role in modulating cardiac-remodeling by limiting excessive fibrosis and protecting CMs from cell death. Methods: We investigated the therapeutic potential of ASPN by using an exogenous recombinant peptide of ASPN (rASPN), testing its effects using an Results: Proteomics revealed that ASPN modulates key pathways involved in apoptosis, non-canonical autophagy, and metabolic reprogramming. Additionally, ASPN influenced immune response pathways and significantly affected TGF-β signaling, a central mediator of cardiac fibrosis and remodeling post-MI. These findings indicate that ASPN plays a multifaceted role in regulating cellular responses to hypoxia and R/I. Conclusions: Our H/R model simulates key aspects of MI and R/I. The protective role of ASPN observed in this model suggests it as a promising candidate for developing cardioprotective therapies to minimize R/I and adverse cardiac-remodeling following MI.