Thromboxane A2 mediates apoptosis in cardiomyocytes via IP3

Abstract

We have shown that the inflammatory mediator thromboxane A2 (TxA2) can induce ventricular arrhythmias that were associated with increased intracellular calcium in cardiomyocytes. We were able to prevent both the arrhythmias and the changes in intracellular calcium by inhibiting inositol trisphosphate (IP3) signaling. In this investigation, we sought to determine if TxA2 receptor (TxA2R) activation would trigger apoptosis in isolated adult mouse cardiomyocytes. Our hypothesis is that TxA2R‐stimulation induces IP3 formation and subsequent IP3 receptor activation triggers apoptosis. We found that TxA2Rs were expressed in the ventricles and that there was a concentration dependent increase in cell death (Trypan blue and MTT assays) following treatment with the TxA2 mimetic U46619 (0.1–10 μM). We have confirmed that TxA2‐induced death was apoptotic via cleaved caspase‐3 and TUNEL staining. Treatment of cells with the TxA2R antagonist SQ29548 and the IP3 inhibitors Gentamycin and 2‐APB eliminated the increase in apoptosis by U46619. In conclusion, our data suggests that: 1) TxA2‐induced cell death is mediated in part by apoptosis and 2) the IP3 pathway is a novel mediator of apoptosis in cardiomyocytes. These findings may provide important therapeutic targets for inflammatory‐induced cardiac apoptosis that can lead to heart failure. (AHA 11SDG5330016 to MJW)