Inactivation of 14-3-3 Protein Exacerbates Cardiac Hypertrophy and Fibrosis through Enhanced Expression of Protein Kinase C .BETA.2 in Experimental Diabetes

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  • Gurusamy Narasimman
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
  • Watanabe Kenichi
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
  • Ma Meilei
    Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences
  • Zhang Shaosong
    Departments of Cell Biology and Physiology, Center for Cardiovascular Research, Washington University School of Medicine
  • Muslin Anthony J.
    Departments of Cell Biology and Physiology, Center for Cardiovascular Research, Washington University School of Medicine
  • Kodama Makoto
    First Department of Medicine, Niigata University School of Medicine
  • Aizawa Yoshifusa
    First Department of Medicine, Niigata University School of Medicine

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  • Inactivation of 14-3-3 Protein Exacerbates Cardiac Hypertrophy and Fibrosis through Enhanced Expression of Protein Kinase C β2 in Experimental Diabetes
  • Inactivation of 14 3 3 Protein Exacerbates Cardiac Hypertrophy and Fibrosis through Enhanced Expression of Protein Kinase C ベータ 2 in Experimental Diabetes

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Diabetic cardiomyopathy is associated with cardiac hypertrophy and fibrosis. Activation of protein kinase C (PKC) has been implicated in the diabetes-induced cardiovascular complications. PKCβ2 isoform is preferentially found to be activated in the diabetic myocardium. However, the role of PKCβ2 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 PKCβ2 in the diabetic myocardium. Cardiac myocyte diameter, content of cardiac fibrosis, left ventricular tissue expressions of atrial natriuretic peptide, transforming growth factor β1, collagen III and PKCβ2 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 PKCβ2 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 PKCβ2 in the diabetic myocardium.

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