Enhancing Cardiac Repair with ENPP1 Inhibition

A recent study offers insights into a novel approach to cardiac repair by inhibiting ENPP1, an enzyme critical to regulating extracellular nucleotide metabolism. MediLumine’s Fenestra HDVC contrast-enhanced microCT was used in this study to characterize cardiovascular disease in a murine model.

Exploring ENPP1 Inhibition for Cardiac Repair

This study suggests a broader approach, emphasizing cellular crosstalk and the regulation of metabolism as a key therapeutic target. ENPP1 inhibition emerged as a promising strategy to drive these broader beneficial effects. As the primary ectonucleotidase that catalyzes ATP hydrolysis, ENPP1 was identified as the main enzyme responsible for mediating extracellular ATP breakdown, making it an attractive target for metabolic intervention.

Through hENPP1mAb, a monoclonal antibody that selectively inhibits ENPP1, researchers observed several positive outcomes, including decreased fibroblast activation, reduced extracellular matrix (ECM) gene expression, enhanced glycolysis, and improved myocyte contractility. The study noted a marked reduction in fibrosis and ECM deposition without any increase in cardiac rupture risk, which is a common concern in the early stages of MI. The timing of peak ENPP1 expression—seven days post-infarction—likely aligns well with this intervention, as it occurs after the highest risk period for rupture. This approach could translate to a powerful treatment strategy for enhancing heart repair and preventing post-MI heart failure in humans.

Fenestra HDVC and Murine Model Imaging

The use of Fenestra HDVC contrast-enhanced microCT enabled detailed visualization and assessment of cardiovascular disease within the murine model, providing researchers with an advanced means to characterize how metabolic interventions impact cardiac health post-infarction. This imaging technology excels in providing high-resolution, non-destructive images of soft tissues in vivo, making it ideal for visualizing subtle cardiac tissue changes and structural remodeling post-MI. With Fenestra HDVC, the researchers could track the effects of ENPP1 inhibition on heart structure and function over time, offering a more comprehensive understanding of how the cardiac repair process unfolds without the use of alkaline metal microCT contrast agents that can lead to release of inflammatory cytokines following uptake by the mononuclear phagocytic cells of liver.

*Image of heart used under creative commons cc-by license

Full Citation

Li S, Tao B, Wan J, Dorshkind K, Xu S, Deb A. A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction. Cell Reports Medicine. 2024;5(10):101795. doi:10.1016/j.xcrm.2024.101795. Epub 2024 Oct 24.