Article

Protein kinase C? 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: 4.66). 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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    • "Whilst the significance of IP 3 in heart disease remains controversial, PKC family members are clearly implicated in pathology. Heightened activity of PKCα in failed myocardium is associated with contractile failure [10] [11], PKCδ promotes cell death pathways and PKCε is generally regarded as cardioprotective [12] [13]. Despite being the primary effector of Gq and being the upstream activator of PKC, the involvement of PLCβ subtypes in cardiac disease has received little scrutiny. "
    Dataset: JMCC2015a

    Full-text · Dataset · May 2015
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    • "Whilst the significance of IP 3 in heart disease remains controversial, PKC family members are clearly implicated in pathology. Heightened activity of PKCα in failed myocardium is associated with contractile failure [10] [11], PKCδ promotes cell death pathways and PKCε is generally regarded as cardioprotective [12] [13]. Despite being the primary effector of Gq and being the upstream activator of PKC, the involvement of PLCβ subtypes in cardiac disease has received little scrutiny. "
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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.
    Full-text · Article · Apr 2015 · Journal of Molecular and Cellular Cardiology
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    • "PKC-α on the other hand, has been reported by many to be a pro-survival isoform that promotes cell survival via direct phosphorylation of Akt at serine 473 [38] and also as a negative regulator of cardiac functional efficiency shown by its increased expression in various models of cardiac injury or failure [12], [39]. PKC-α dependent regulation of cardiomyocyte hypertrophy requires ERK-1/2 activation [9] for cardio-protection during ischemia reperfusion injury through activation of the several anti-apoptotic and pro-survival signaling cascades [40]. "
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    ABSTRACT: A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week male Balb/c mice (Mus musculus) models, by reverse transcriptase-PCR, western blot analysis and M-mode echocardiography for cardiac function analysis. PKC-δ was significantly induced during pathological hypertrophy while PKC-α was exclusively activated during physiological hypertrophy in our study. PKC-δ activation during pathological hypertrophy resulted in cardiomyocyte apoptosis leading to compromised cardiac function and on the other hand, activation of PKC-α during physiological hypertrophy promoted cardiomyocyte growth but down regulated cellular apoptotic load resulting in improved cardiac function. Reversal in PKC-isoform with induced activation of PKC-δ and simultaneous inhibition of phospho-PKC-α resulted in an efficient myocardium to deteriorate considerably resulting in compromised cardiac function during physiological hypertrophy via augmentation of apoptotic and fibrotic load. This is the first report where PKC-α and -δ have been shown to play crucial role in cardiac adaptation during physiological and pathological hypertrophy respectively thereby rendering compromised cardiac function to an otherwise efficient heart by conditional reversal of their activation.
    Full-text · Article · Aug 2014 · PLoS ONE
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