Lysophosphatidylserine induces necrotic cell death in pressure-overloaded hearts via G protein-coupled receptor 34. Mus musculus

Heart failure is a leading cause of mortality in developed countries. Cell death is a key player in the development of heart failure. Calcium-independent phospholipase A2beta (iPLA2beta) produces lipid mediators by catalyzing lipids, and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2beta induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated though its receptor, G protein-coupled receptor 34 (GRP34). Cardiomyocyte-specific iPLA2beta-deficient mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2beta-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2beta-deficient hearts. Knockdown of Grp34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal rat cardiomyocytes, while the ablation of Grp34 reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA2beta-lysophosphatidylserine-G protein-coupled receptor 34-necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.