title: Depletion of 14-3-3 protein exacerbates cardiac oxidative stress, inflammation and remodeling process via modulation of MAPK/NF-ĸB signaling pathways after streptozotocin-induced diabetes mellitus.
abstract: Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. The aim of the study presented here was to clarify the role of 14-3-3 protein in the mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling pathway after experimental diabetes by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3). Significant p-p38 MAPK activation in DN 14-3-3 mice compared to wild type mice (WT) after diabetes induction and with a corresponding up regulation of its downstream effectors, p-MAPK activated protein kinase 2 (MAPKAPK-2). Marked increases in cardiac hypertrophy, fibrosis and inflammation were observed with a corresponding up-regulation of atrial natriuretic peptide, osteopontin, connective tissue growth factor, tumor necrosis factor α, interleukin (IL)-1β, IL-6 and cellular adhesion molecules. Moreover, reactive oxygen species, left ventricular expression of NADPH oxidase subunits, p22 phox, p67 phox, and Nox4, and lipid peroxidation levels were significantly increased in diabetic DN 14-3-3mice compared to diabetic WT mice. Furthermore, myocardial NF-κB activation, inhibitor of kappa B-α degradation and mRNA expression of proinflammatory cytokines were significantly increased in DN 14-3-3 mice compared to WT mice after diabetes induction. In conclusion, our data suggests that depletion of 14-3-3 protein induces cardiac oxidative stress, inflammation and remodeling after experimental diabetes induction mediated through p38 MAPK, MAPKAPK-2 and NF-κB signaling.
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata city, Japan.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.forename: Vijayasree V
authors.initials: VV
authors.lastname: Giridharan
authors.forename: Flori R
authors.initials: FR
authors.lastname: Sari
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.forename: Punniyakoti T
authors.initials: PT
authors.lastname: Veeraveedu
authors.forename: Ganesh N
authors.initials: GN
authors.lastname: Pandian
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Palaniyandi
authors.forename: Meilei
authors.initials: M
authors.lastname: Ma
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Narasimman
authors.initials: N
authors.lastname: Gurusamy
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D048948:14-3-3 Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2