Sequeira, V, Najafi, A, McConnell, M et al. (10 more authors) (2015) Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness. Journal of Physiology, 593 (17). 3899 - 3916. ISSN 0022-3751
Abstract
Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society. This is the peer reviewed version of the following article: Sequeira, V, Najafi, A, McConnell, M, Fowler, ED, Bollen, IAE, Wust, RCI, dos Remedios, C, Helmes, M, White, E, Stienen, GJM, Tardiff, J, Kuster, DWD and Van der Velden, J (2015) Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness. Journal of Physiology, 593 (17). 3899 - 3916. ISSN 0022-3751, which has been published in final form at http://dx.doi.org/10.1113/JP270354. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. |
Keywords: | calcium transients; cardiac contractility and energetics; cardiomyocyte contractile reserve |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Jun 2015 10:58 |
Last Modified: | 24 Oct 2016 16:07 |
Published Version: | http://dx.doi.org/10.1113/JP270354 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1113/JP270354 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:87265 |