The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism
Sonia Spinelli,
Lucrezia Guida,
Tiziana Vigliarolo,
Mario Passalacqua,
Giulia Begani,
Mirko Magnone,
Laura Sturla,
Andrea Benzi,
Pietro Ameri,
Edoardo Lazzarini,
Claudia Bearzi,
Roberto Rizzi,
Elena Zocchi
Affiliations
Sonia Spinelli
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Lucrezia Guida
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Tiziana Vigliarolo
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Mario Passalacqua
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Giulia Begani
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Mirko Magnone
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Laura Sturla
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Andrea Benzi
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Pietro Ameri
Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy
Edoardo Lazzarini
Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Via Tesserete 48, 6500 Bellinzona, Switzerland
Claudia Bearzi
Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Via Fratelli Cervi 93, 20054 Milan, Italy
Roberto Rizzi
Fondazione Istituto Nazionale di Genetica Molecolare, Via F. Sforza 35, 20122 Milan, Italy
Elena Zocchi
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia.
