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TNFR2‐mediated Survival via Orai1‐3‐dependent Calcium Influx in Compensated Cardiac Hypertrophy
Author(s) -
Pavoine Catherine,
Keck Mathilde,
Mougenot Nathalie,
Fuand Alexandre,
Atassi Fabrice,
Barbier Camille,
Lompré AnneMarie,
Hulot JeanSébastien
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb486
Subject(s) - orai1 , chemistry , microbiology and biotechnology , in vivo , inflammation , pharmacology , phospholipase a2 , muscle hypertrophy , medicine , endocrinology , endoplasmic reticulum , biology , biochemistry , stim1 , enzyme
Compensated cardiac hypertrophy (CH) is associated with the emergence of Orai1‐3 voltage‐ and store‐independent Ca2+ entry activated by Arachidonic Acid (AA). Our objectives were to determine Orai1‐3 activating pathways and to evaluate the protective potential of Orai1‐3 to limit transition to heart failure (HF). We considered tumor necrosis factor α (TNFα) as a stimulatory candidate since it is a known enhancer of cytosolic phospholipase A2 (cPLA2) activity and a major component of the inflammatory response that develops with CH. We performed Ca2+ imaging studies and measure Orai1‐3‐dependent Ca2+ influx on adult rat cardiomyocytes (CM) which developed hypertrophy in response to either in‐vitro or in‐vivo chronic treatment with isoproterenol. Orai1‐3 were modulated using pharmacological inhibitor in‐vitro or intra‐cardiac delivery of Orai1 or 3 silencing RNA in‐vivo. We show that TNFα enhances Orai‐dependent Ca2+ influx in hypertrophic CM via the TNFR2 pathway as attested by inhibition with neutralizing anti‐TNFR2 antibodies but insensitivity to anti‐TNFR1 antibodies. TNFα activation of Orai‐dependent Ca2+ influx is impaired upon incubation with a cPLA2 inhibitor or a lipoxygenase inhibitor, highlighting the role of AA synthesis and further lipoxygenase‐dependent metabolism. Finally, TNFR2‐induced activation of Orai1‐3‐dependent Ca2+ influx increases survival of hypertrophic CM to oxidative stress. Our study highlights a close interplay between early inflammation and adaptative Orai1‐3‐dependent Ca2+ influx. These data further recommend identification of pharmacological interventions targeting Orai1‐3 to limit transition to HF.