title: Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress.
abstract: Increased osteopontin (OPN) expression associates with increased myocyte apoptosis and myocardial dysfunction. The objective of this study was to identify the receptor for OPN and get insight into the mechanism by which OPN induces cardiac myocyte apoptosis. Adult rat ventricular myocytes (ARVMs) 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 ARVMs. OPN co-immunoprecipitated with CD44 receptors, not with β1 or β3 integrins. Proximity ligation assay confirmed interaction of OPN with CD44 receptors. 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 in myocyte-specific manner associated with decreased left ventricular function and increased myocyte apoptosis. In the heart, OPN expression increased JNKs and caspase-12 activities, and expression of Bax and Gadd153. Thus, OPN, acting via CD44 receptors, induces apoptosis in myocytes via the involvement of mitochondrial death pathway and ER stress.
authors: Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee;
authors: Suman
authors: S
authors: Dalal
authors: Qinqin
authors: Q
authors: Zha
authors: Christopher R
authors: CR
authors: Daniels
authors: Rebecca J
authors: RJ
authors: Steagall
authors: William L
authors: WL
authors: Joyner
authors: Alain-Pierre
authors: AP
authors: Gadeau
authors: Mahipal
authors: M
authors: Singh
authors: Krishna
authors: K
authors: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12; D061945:Caspase Inhibitors / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000187:drug effects / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D053495:Osteopontin / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000473:pathology
chemical_list: D061945:Caspase Inhibitors; D018960:Hyaluronan Receptors; D047428:Protein Kinase Inhibitors; D053495:Osteopontin; D048031:JNK Mitogen-Activated Protein Kinases; D053454:Caspase 12
keywords: CD44; ER stress; JNKs; apoptosis; myocyte; osteopontin