COX-2 optimizes cardiac mitochondrial biogenesis and exerts a cardioprotective effect during sepsis.

BACKGROUND

Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E (PGE), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function.

OBJECTIVE

This study aims to demonstrate that COX-2/PGE can protect against septic cardiomyopathy by regulating mitochondrial function.

METHODS

Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection.

RESULTS

The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE on the heart was also verified in the septic mice.

CONCLUSION

Collectively, these results suggested that COX-2/PGE pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE only acted as an inflammatory factor.