Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34

Ryuta Sugihara, Manabu Taneike, Tomokazu Murakawa, Takahito Tamai, Hiromichi Ueda, Rika Kitazume-Taneike, Takafumi Oka, Yasuhiro Akazawa, Hiroki Nishida, Kentaro Mine, Ayana Hioki, Jumpei Omi, Shigemiki Omiya, Junken Aoki, Kazutaka Ikeda, Kazuhiko Nishida, Makoto Arita, Osamu Yamaguchi, Yasushi Sakata and Kinya Otsu ()
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Ryuta Sugihara: Osaka University Graduate School of Medicine
Manabu Taneike: Osaka University Graduate School of Medicine
Tomokazu Murakawa: Osaka University Graduate School of Medicine
Takahito Tamai: Osaka University Graduate School of Medicine
Hiromichi Ueda: Osaka University Graduate School of Medicine
Rika Kitazume-Taneike: Osaka University Graduate School of Medicine
Takafumi Oka: Osaka University Graduate School of Medicine
Yasuhiro Akazawa: Osaka University Graduate School of Medicine
Hiroki Nishida: Osaka University Graduate School of Medicine
Kentaro Mine: Osaka University Graduate School of Medicine
Ayana Hioki: Osaka University Graduate School of Medicine
Jumpei Omi: The University of Tokyo
Shigemiki Omiya: King’s College London British Heart Foundation Centre of Excellence
Junken Aoki: The University of Tokyo
Kazutaka Ikeda: RIKEN Center for Integrative Medical Sciences (IMS)
Kazuhiko Nishida: King’s College London British Heart Foundation Centre of Excellence
Makoto Arita: RIKEN Center for Integrative Medical Sciences (IMS)
Osamu Yamaguchi: Ehime University Graduate School of Medicine
Yasushi Sakata: Osaka University Graduate School of Medicine
Kinya Otsu: King’s College London British Heart Foundation Centre of Excellence

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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 A2β (iPLA2β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA2β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2β-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 iPLA2β—lysophosphatidylserine—GPR34—necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.

Date: 2023
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DOI: 10.1038/s41467-023-40201-4

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