title: Inactivation of 14-3-3 protein exacerbates cardiac hypertrophy and fibrosis through enhanced expression of protein kinase C beta 2 in experimental diabetes.
abstract: Diabetic cardiomyopathy is associated with cardiac hypertrophy and fibrosis. Activation of protein kinase C (PKC) has been implicated in the diabetes-induced cardiovascular complications. PKCbeta2 isoform is preferentially found to be activated in the diabetic myocardium. However, the role of PKCbeta2 in diabetic cardiomyopathy is not clear. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic and checkpoint control pathways, and have been shown to bind with PKC isozymes and negatively regulate their enzymatic activities. The present study tests whether 14-3-3 protein regulates cardiac hypertrophy and fibrosis in streptozotocin (STZ)-induced diabetic mice, using transgenic mice with cardiac specific over-expression of dominant negative (DN) 14-3-3 protein. In addition, we examined the relationship between 14-3-3 protein and PKCbeta2 in the diabetic myocardium. Cardiac myocyte diameter, content of cardiac fibrosis, left ventricular tissue expressions of atrial natriuretic peptide, transforming growth factor beta1, collagen III and PKCbeta2 were significantly elevated 28 and 56 d after STZ injection in transgenic DN-14-3-3 mice, when compared to their non-transgenic counterparts. These results clearly demonstrate that the functional inactivation of 14-3-3 protein in DN-14-3-3 mice exacerbates diabetes-induced cardiac hypertrophy and fibrosis. The exacerbations of cardiac hypertrophy and fibrosis were significantly and positively correlated with the enhanced expression of PKCbeta2 in DN-14-3-3 mice. Our results indicate for the first time that 14-3-3 protein negatively regulates cardiac hypertrophy and fibrosis, possibly through controlling the expression of PKCbeta2 in the diabetic myocardium.
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan.
authors.forename: Narasimman
authors.initials: N
authors.lastname: Gurusamy
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Meilei
authors.initials: M
authors.lastname: Ma
authors.forename: Shaosong
authors.initials: S
authors.lastname: Zhang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D048948:14-3-3 Proteins / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D011493:Protein Kinase C