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Cardiorenal Protection in Diabetes Mellitus

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Molecular Defects in Cardiovascular Disease

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Abstract

Diabetic cardiomyopathy is a major complication of diabetes that is independent of high blood pressure or atherosclerosis. In addition to diastolic dysfunction, the diabetic heart is more susceptible to oxidative stress. Hyperglycemia (HG) dominates the pathophysiology and clinical course of type 1 and type 2 Diabetes. An important question concerns the signals used by high concentrations of extracellular glucose to alter the biochemical and mechanical properties of cardiac muscle cells. Recruitment of the Protein Kinase C (PKC) family of serine–threonine kinases is an integral component of the signaling events that direct the cardiac phenotype expressed during postnatal cardiac development and in response to pathological stimuli. We have described that genetically engineered mice with cardiac-specific expression of an isozyme-specific PKC-ε translocation activator exhibit protection from hyperglycemia-induced apoptosis and LV dysfunction. The ψε-RACK peptide facilitated the intracellular trafficking of PKC-ε, and thereby prevented hyperglycemia-mediated decreases in immunoreactivity in both membrane and mitochondrial compartments. A unifying hypothesis has been proposed for the development of diabetic complications, based on the overproduction of Reactive Oxygen Species (ROS). The adapter protein p66Shc A is a part of a signal transduction pathway and may be a key component of the cell signal response to oxidative stress contributing to the lifespan in mammals. p66ShcA functions as a potentially harmful regulatory gene, which is required for the generation of HG-induced oxidative stress and apoptosis. At high ambient glucose (HG), p66ShcA-deficient cells exhibit resistance to HG-induced ROS generation and attenuation in the amplitude of the kinetic curves for intracellular ROS metabolism, indicative of the pivotal role of WTp66ShcA in the generation of HG oxidant stress. Inhibition of WTp66ShcA function shuts down HG-induced ROS production in cytosolic and mitochondrial compartments.

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Authors and Affiliations

  1. Department of Nephrology, Ochsner Clinic Foundation, New Orleans, LA, USA

    Himanshu Vashistha & Leonard G. Meggs

  2. Division of Nephrology, Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY, USA

    Ashwani Malhotra

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  1. Himanshu Vashistha
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  2. Leonard G. Meggs
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  3. Ashwani Malhotra
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Correspondence to Ashwani Malhotra .

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Editors and Affiliations

  1. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

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Vashistha, H., Meggs, L.G., Malhotra, A. (2011). Cardiorenal Protection in Diabetes Mellitus. In: Dhalla, N., Nagano, M., Ostadal, B. (eds) Molecular Defects in Cardiovascular Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7130-2_26

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