Postoperative administration of 2,5-dimethylcelecoxib attenuates ischemia-reperfusion injury-induced cardiac dysfunction.

Abstract

Ischemia-reperfusion (I/R) following reperfusion therapy for ischemic heart disease is a driver of adverse cardiac remodeling and eventual heart failure. We investigated the therapeutic potential of 2,5-dimethylelcelecoxib (DM-C) to prevent cardiac remodeling in a mouse model of cardiac I/R injury. Male C57BL/6 mice were subjected to 30 min of left anterior descending coronary artery ligation followed by reperfusion. Immediately upon awakening, mice received a single oral administration of either vehicle or 150 mg/kg DM-C. This was followed by dietary administration of vehicle or 1000 ppm DM-C. Post-reperfusion administration of DM-C significantly attenuated cardiac remodeling, as demonstrated by improved left ventricular function and reduced cardiac fibrosis and hypertrophy. Mechanistically, DM-C transiently increased the accumulation of CD68-positive macrophages in the injured myocardium, potentially facilitating resolution of inflammation. DM-C also suppressed α-smooth muscle actin-expressing myofibroblast accumulation and downregulated extracellular matrix components. While DM-C treatment tended to mitigate I/R-induced mitochondrial structural destruction and dysfunction, it did not directly improve mitochondrial function in in vitro hypoxia-reoxygenation model. These findings suggest that DM-C suppresses post-I/R cardiac remodeling and dysfunction by modulating inflammatory and fibrotic responses and indirectly supporting mitochondrial integrity, underscoring its potential as a therapeutic agent for I/R injury-induced heart failure.