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      Role of Differential Signaling Pathways and Oxidative Stress in Diabetic Cardiomyopathy

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          Abstract

          Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.

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          Most cited references150

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          Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.

          C Marshall (1995)
          A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions.
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            ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis.

            Apoptosis signal-regulating kinase (ASK) 1 is activated in response to various cytotoxic stresses including TNF, Fas and reactive oxygen species (ROS) such as H(2)O(2), and activates c-Jun NH(2)-terminal kinase (JNK) and p38. However, the roles of JNK and p38 signaling pathways during apoptosis have been controversial. Here we show that by deleting ASK1 in mice, TNF- and H(2)O(2)-induced sustained activations of JNK and p38 are lost in ASK1(-/-) embryonic fibroblasts, and that ASK1(-/-) cells are resistant to TNF- and H(2)O(2)-induced apoptosis. TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1-JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.
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              Left ventricular hypertrophy: pathogenesis, detection, and prognosis.

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                Author and article information

                Journal
                Curr Cardiol Rev
                CCR
                Current Cardiology Reviews
                Bentham Science Publishers Ltd
                1573-403X
                1875-6557
                November 2010
                : 6
                : 4
                : 280-290
                Affiliations
                [1 ]Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata City, Japan
                [2 ]Cardiovascular Research Center, University of Connecticut School of Medicine, USA
                [3 ]First Department of Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
                Author notes
                [* ]Address correspondence to this author at the Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata city, 956-8603, Japan; Tel: +81-250-25-5267, Fax: +81-250-25-5021, E-mail: watanabe@ 123456nupals.ac.jp
                Article
                CCR-6-280
                10.2174/157340310793566145
                3083809
                22043204
                4aa75f08-3c64-4e64-a7ef-cd6f17d1eea2
                © 2010 Bentham Science Publishers Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 September 2010
                : 3 September 2010
                : 15 September 2010
                Categories
                Article

                Cardiovascular Medicine
                diabetes mellitus,cardiomyopathy,hypertrophy.,apoptosis,oxidative stress
                Cardiovascular Medicine
                diabetes mellitus, cardiomyopathy, hypertrophy., apoptosis, oxidative stress

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