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Osteopontin Stimulates Cardiac Myocyte Apoptosis via the Involvement of ER Stress and Mitochondrial Death Pathway
Author(s) -
Dalal Suman,
Zha Qinqin,
Daniels Christopher R.,
Steagall Rebecca J.,
Das Bhudev C.,
Gadeau AlainPierre,
Joyner William L.,
Singh Mahipal,
Singh Krishna
Publication year - 2013
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.27.1_supplement.727.3
Subject(s) - osteopontin , apoptosis , unfolded protein response , microbiology and biotechnology , myocyte , biology , endoplasmic reticulum , caspase 3 , chemistry , programmed cell death , endocrinology , medicine , biochemistry
Increased osteopontin (OPN; matricellular protein) expression associates with myocyte apoptosis and myocardial dysfunction. The objective of this study was to identify OPN receptor, and understand the mechanism by which OPN induces myocyte apoptosis. Adult rat ventricular myocytes (ARVM) and transgenic mice expressing OPN in a myocyte‐specific manner were used for in vitro and in vivo studies. Treatment with purified OPN (20 nM) protein or adenoviral‐mediated OPN expression induced apoptosis in ARVM. OPN co‐immunoprecipitated with CD44 receptor. Neutralizing anti‐CD44 antibodies inhibited OPN‐stimulated apoptosis. OPN activated JNKs, and increased expression of Bax and levels of cytosolic cytochrome c suggesting involvement of mitochondrial death pathway. OPN increased endoplasmic reticulum (ER) stress, as evidenced by increased expression of Gadd153 and activation of caspase‐12. Inhibition of JNKs using SP600125 or ER stress using salubrinal or caspase‐12 inhibitor significantly reduced OPN‐stimulated apoptosis. Expression of OPN in adult mouse heart associated with increased myocyte apoptosis and LV dysfunction. In the heart, OPN expression increased JNKs and caspase‐12 activities, and expression of Bax and Gadd153. OPN, acting via CD44 receptors, induces apoptosis in myocytes via the involvement of ER stress and mitochondrial death pathway.