Article

Protein kinase Cα as a heart failure therapeutic target.

Department of Pediatrics, Division of Molecular Cardiovascular Biology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.22). 10/2010; 51(4):474-8. DOI: 10.1016/j.yjmcc.2010.10.004
Source: PubMed

ABSTRACT Heart failure afflicts ~5 million people and causes ~300,000 deaths a year in the United States alone. Heart failure is defined as a deficiency in the ability of the heart to pump sufficient blood in response to systemic demands, which results in fatigue, dyspnea, and/or edema. Identifying new therapeutic targets is a major focus of current research in the field. We and others have identified critical roles for protein kinase C (PKC) family members in programming aspects of heart failure pathogenesis. More specifically, mechanistic data have emerged over the past 6-7 years that directly implicate PKCα, a conventional PKC family member, as a nodal regulator of heart failure propensity. Indeed, deletion of the PKCα gene in mice, or its inhibition in rodents with drugs or a dominant negative mutant and/or inhibitory peptide, has shown dramatic protective effects that antagonize the development of heart failure. This review will weigh all the evidence implicating PKCα as a novel therapeutic target to consider for the treatment of heart failure. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

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    ABSTRACT: Introduction Heart failure (HF) is a progressive, essentially irreversible disease in which the capacity of the heart to provide adequate blood supply is compromised. Along with its associated pathologies, heart failure contributes substantially to the cost of healthcare and the cost worldwide is rising rapidly. 1 The failing myocardium exhibits a range of pathologies, all of which need to be therapeutically targeted for the successful management of the condition. Treatment regimens commonly include angiotensin converting enzyme (ACE) inhibitors and β-adrenergic receptor blockers, and may incorporate an ino-tropic agent to enhance end organ perfusion. 2,3 In patients with impaired systolic function, inotropic agents provide an improvement in cardiac performance, but this is often at a cost of increased myocardial oxygen consumption, potentially increasing the likelihood of ischemia and arrhythmia. 4 New types of inotropic agents are clearly needed. The failing myocardium exhibits a number of changes that contribute to contractile dysfunction. Included among these are loss of functional myocytes 5 and extracellular matrix deposition 6 ; but in addition to these structural changes, there are signal-ing changes within the myocytes themselves, which contribute to contractile dysfunction. These intracellular changes provide potential start points for developing novel therapeutic strategies. The overarching idea is that, by reversing the intracellular changes that accompany the transition to HF, it may be possible to provide well-tolerated improvements in the pump performance. In general, these would be used in combination with agents that target other aspects of the complex disease of HF. Sarcoplasmic Reticulum Ca 2+ as a Target for Inotropic Therapy The regulation of cardiac contractile function is orchestrated primarily by the sarcoplasmic reticulum (SR), which provides the Ca 2+ ions to initiate and sustain contraction of the myo-cyte. The cardiac contraction cycle is initiated by Ca 2+ entry via voltage-regulated Ca 2+ channels in the sarcolemma, which provide the trigger Ca 2+ to activate ryanodine receptors on the SR, resulting in release of sufficient Ca 2+ from the SR into the cytosol to initiate contraction during systole. 7 Ca 2+ is subsequently pumped back into the SR by the sarco-endoplasmic reticulum ATPase (SERCA)2a, the activity of which is closely regulated by the phosphorylation status of phospholamban (PLN). PLN is an inhibitor of SERCA2a in the dephosphory-lated state, and this inhibition is relieved by phosphorylation. 8 PLN is phosphorylated, most importantly, by protein kinase A (PKA) on S 16 following activation of β-adrenergic receptors, and its phosphorylation results in heightened SERCA function , accelerated relaxation, and increased SR Ca 2+ content. AbSTRACT: Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca 2+ from the sarcoplasmic reticulum, and this Ca 2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance. keywoRdS: cardiac contractility, inotropic agent, splice variant, protein scaffold CITaTIoN: Woodcock and grubb. novel therapeutic targets in heart Failure: the phospholipase Cβ1b–shank3 interface. CoPYRIgHT: © the authors, publisher and licensee libertas academica limited. this is an open-access article distributed under the terms of the Creative Commons CC-BY-nC 3.0 license. paper subject to independent expert blind peer review by minimum of two reviewers. all editorial decisions made by independent academic editor. upon submission manuscript was subject to anti-plagiarism scanning. prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. this journal is a member of the Committee on publication ethics (COpe). provenance: the authors were invited to submit this paper. published by libertas academica. learn more about this journal. Woodcock and Grubb 12 CliniCal MediCine insights: therapeutiCs 2015:7 The Ca 2+ content of the SR is typically lowered in failing myocytes,
    Clinical Medicine Insights: Therapeutics 03/2015; 2015(7):7-11. DOI:10.4137/CMt.s18480
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    ABSTRACT: The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCβ1b activity to cardiac pathology. PLCβ1b, the alternative splice variant, PLCβ1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG-PLCβ1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCβ1b expression caused a rapid loss of contractility, 4-6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase Cα (PKCα). PLCβ1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCβ1b, but not PLCβ1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca(2+) stores of the sarcoplasmic reticulum. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 04/2015; 84:95-103. DOI:10.1016/j.yjmcc.2015.04.016 · 5.22 Impact Factor

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