Hegab, Z and Mohamed, TMA and Stafford, N and Mamas, M and Cartwright, EJ and Oceandy, D (2017) Advanced glycation end products reduce the calcium transient in cardiomyocytes by increasing production of reactive oxygen species and nitric oxide. FEBS Open Bio, 7 (11). 1672 -1685. ISSN 2211-5463

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Abstract

Advanced glycation end products (AGE) are central to the development of cardiovascular complications associated with diabetes mellitus. AGE may alter cellular function through cross-linking of cellular proteins or by activating the AGE receptor (RAGE). However, the signalling molecules involved during AGE stimulation in cardiomyocytes remain unclear. Here, we investigated the effects of AGE treatment on intracellular calcium homeostasis of isolated cardiomyocytes and studied the activation of signalling molecules involved in this process. Treatment of cardiomyocytes with AGE for 24 h resulted in a dose-dependent reduction in calcium transient amplitude, reaching a maximum 50% reduction at a dose of 1 mg·mL−1. This was accompanied with a 32% reduction in sarcoplasmic reticulum calcium content but without any detectable changes in the expression of major calcium channels. Mechanistically, we observed a significant increase in the production of reactive oxygen species (ROS) in AGE-treated cardiomyocytes and enhancement of NADPH oxidase activity. This was accompanied with activation of p38 kinase and nuclear translocation of NF-κB, and subsequently induction of inducible NO synthase (iNOS) expression, leading to excessive nitric oxide production. Overall, our data reveal the molecular signalling that may underlie the alteration of intracellular calcium homeostasis in cardiac myocytes due to AGE stimulation. This may provide new insights into the pathophysiological mechanisms of the development of diabetic cardiomyopathy.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via Wiley at http://dx.doi.org/10.1002/2211-5463.12284 - please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > RC Internal medicine > RC666 Diseases of the circulatory (Cardiovascular) system
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 16 Nov 2017 10:47
Last Modified: 16 Nov 2017 10:47
URI: http://eprints.keele.ac.uk/id/eprint/4234

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