Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34.
Ryuta SugiharaManabu TaneikeTomokazu MurakawaTakahito TamaiHiromichi UedaRika Kitazume-TaneikeTakafumi OkaYasuhiro AkazawaHiroki NishidaKentaro MineAyana HiokiJumpei OmiShigemiki OmiyaJunken AokiKazutaka IkedaKazuhiko NishidaMakoto AritaOsamu YamaguchiYasushi SakataKinya OtsuPublished in: Nature communications (2023)
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 A 2 β (iPLA 2 β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA 2 β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA 2 β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA 2 β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA 2 β-deficient hearts. Knockdown of Gpr34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal male rat cardiomyocytes, while the ablation of Gpr34 in male mice reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA 2 β-lysophosphatidylserine-GPR34-necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.
Keyphrases
- heart failure
- cell death
- left ventricular
- high glucose
- fatty acid
- endothelial cells
- cardiac resynchronization therapy
- oxidative stress
- diabetic rats
- angiotensin ii
- hypertrophic cardiomyopathy
- left atrial
- blood pressure
- cell cycle arrest
- acute myocardial infarction
- mitral valve
- atrial fibrillation
- aortic stenosis
- risk factors
- acute heart failure
- acute coronary syndrome
- skeletal muscle
- type diabetes
- single cell
- smooth muscle
- high fat diet induced
- data analysis