Ethanol for cardiac ischemia: the role of protein kinase c

Churchill, Eric N.; Disatnik, Marie‐Hélène; Budas, Grant R.; Mochly‐Rosen, Daria

doi:10.1177/1753944708094735

Cited by 11 publications

(16 citation statements)

References 129 publications

(198 reference statements)

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“…Thus, insufficient ethanol washout or metabolism prior to I/R may lead to accumulation of cytotoxic aldehydes that worsen postischemic tissue injury by inactivating enzymes and disrupting structural proteins through the formation of protein adducts [123,124,155]. It has also been suggested that ethanol may activate protein kinase C isoforms that play opposing roles in I/R, with effects dependent on ethanol dose and timing for response evaluations [155]. …”

Section: Toxic Ethanol Metabolites and Cardioprotectionmentioning

confidence: 99%

Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms

Krenz¹,

Korthuis²

2012

Journal of Molecular and Cellular Cardiology

141

148

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While ethanol intake at high levels (3-4 or more drinks), either in acute (occasional binge drinking) or chronic (daily) settings, increases the risk for myocardial infarction and ischemic stroke, an inverse relationship between regular consumption of alcoholic beverages at light to moderate levels (1-2 drinks per day) and cardiovascular risk has been consistently noted in a large number of epidemiologic studies. Although initially attributed to polyphenolic antioxidants in red wine, subsequent work has established that the ethanol component contributes to the beneficial effects associated with moderate intake of alcoholic beverages regardless of type (red versus white wine, beer, spirits). Concerns have been raised with regard to interpretation of epidemiologic evidence for this association including heterogeneity of the reference groups examined in many studies, different lifestyles of moderate drinkers versus abstainers, and favorable risk profiles in moderate drinkers. However, better controlled epidemiologic studies and especially work conducted in animal models and cell culture systems have substantiated this association and clearly established a cause and effect relationship between alcohol consumption and reductions in tissue injury induced by ischemia/reperfusion (I/R), respectively. The aims of this review are to summarize the epidemiologic evidence supporting the effectiveness of ethanol ingestion in reducing the likelihood of adverse cardiovascular events such as myocardial infarction and ischemic stroke, even in patients with co-existing risk factors, to discuss the ideal quantities, drinking patterns, and types of alcoholic beverages that confer protective effects in the cardiovascular system, and to review the findings of recent experimental studies directed at uncovering the mechanisms that underlie the cardiovascular protective effects of antecedent ethanol ingestion. Mechanistic interrogation of the signaling pathways invoked by antecedent ethanol ingestion may point the way towards development of new therapeutic approaches that mimic the powerful protective effects of socially relevant alcohol intake to limit I/R injury, but minimize the negative psychosocial impact and pathologic outcomes that also accompany consumption of ethanol.

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Section: Toxic Ethanol Metabolites and Cardioprotectionmentioning

confidence: 99%

Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms

Krenz¹,

Korthuis²

2012

Journal of Molecular and Cellular Cardiology

141

148

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“…Tissue extract was centrifuged at 700 g to pellet nuclei and unbroken cellular debris, followed by centrifugation at 10,000 g to collect mitochondrial-enriched fractions, as described. 73 …”

Section: Experimental Methodsmentioning

confidence: 99%

Selective Phosphorylation Inhibitor of Delta Protein Kinase C–Pyruvate Dehydrogenase Kinase Protein–Protein Interactions: Application for Myocardial Injury in Vivo

Qvit

Disatnik

Sho³

et al. 2016

J. Am. Chem. Soc.

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Protein kinases regulate numerous cellular processes, including cell growth, metabolism and cell death. Because the primary sequence and the three-dimensional structure of many kinases are highly similar, the development of selective inhibitors for only one kinase is challenging. Furthermore, many protein kinases are pleiotropic, mediating diverse and sometimes even opposing functions by phosphorylating multiple protein substrates. Here, we set up to develop an inhibitor of a selective protein kinase phosphorylation of only one of its substrates. Focusing on the pleiotropic delta protein kinase C (δPKC), we used a rational approach to identify a distal docking site on δPKC for its substrate, pyruvate dehydrogenase kinase (PDK). We reasoned that an inhibitor of PDK's docking should selectively inhibit the phosphorylation of only PDK without affecting phosphorylation of the other δPKC substrates. Our approach identified a selective inhibitor of PDK docking to δPKC with an in vitro Kd of ~50 nM and reducing cardiac injury IC 50 of ~5 nM. This inhibitor, which did not affect the phosphorylation of other δPKC substrates even at 1 µM, demonstrated that PDK phosphorylation alone is critical for δPKC-mediated injury by heart attack. The approach we describe is likely applicable for the identification of other substrate-specific kinase inhibitors. Graphical Abstract *Corresponding Author. mochly@stanford.edu. ASSOCIATED CONTENT Supporting Information. Experimental details, additional figures and data are available free of charge via the Internet at http:// pubs.acs.org. Author ContributionsAll authors have given approval to the final version of the manuscript.The authors declare that no competing interests exist. HHS Public AccessAuthor manuscript J Am Chem Soc. Author manuscript; available in PMC 2016 October 14. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript INTORDUCTIONThe protein kinases super family accounts for approximately 2% of the eukaryotic genes and about 518 protein kinases are predicted in the human kinome. 1 Protein kinases catalyzed phosphorylation, the transfer of the γ-phosphoryl group from adenosine triphosphate (ATP) to the hydroxyl group of defined amino acid, which regulated many biological processes, including metabolism, transcription, cell cycle progression, and differentiation. Phosphorylation is the most widespread type of post-translational modification in signal transduction with over 500,000 potential phosphorylation sites for any given kinase in the human proteome and 25,000 phosphorylation events described for 7,000 human proteins. 2,3 Phosphorylation is mediated by the catalytic domain that consists of a small N-terminal lobe of β-sheets, a larger C-terminal lobe of α-helices, and the ATP binding site in a cleft between the two lobes. 4 Many kinase inhibitors target the highly conserved ATP-binding pocket. 5 However, since the catalytic domain of most eukaryotic kinases is structurally similar, developing specific protein kinase inhibitors that target the c...

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“…Support for this concept is provided by the observation that pretreatment either with ethanol or with a PKCe activator before undergoing I/R resulted in the phosphorylation and thus activation of aldehyde dehydrogenase-2 (ALDH2), an effect that was inversely correlated to the extent of ischemic tissue damage [57]. These findings suggest that insufficient ethanol washout or metabolism prior to I/R may lead to accumulation of cytotoxic aldehydes that worsen postischemic tissue injury by inactivating enzymes and disrupting structural proteins through the formation of protein adducts [65,66,259,260]. These findings suggest that insufficient ethanol washout or metabolism prior to I/R may lead to accumulation of cytotoxic aldehydes that worsen postischemic tissue injury by inactivating enzymes and disrupting structural proteins through the formation of protein adducts [65,66,259,260].…”

Section: Ethanol Consumption and Ischemic Diseasementioning

confidence: 99%

Cell Survival Programs and Ischemia /Reperfusion: Hormesis, Preconditioning, and Cardioprotection

Krenz¹,

Baines²,

Kalogeris³

et al. 2013

Colloquium Series on Integrated Systems Physiology: From Molecule to Function

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ii This e-book is an original work commissioned for the Colloquium Digital Library of Life Sciences, a curated collection of time-saving pedagogical resources for researchers and students who want to quickly get up to speed in a new area of life science/biomedical research. Each e-book available in Colloquium is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these resources 'Lectures' because authors are asked to provide an authoritative, state-of-the-art overview of their area of expertise, in a manner that is accessible to a broad, diverse audience of scientists (similar to a plenary or keynote lecture at a symposium/meeting/colloquium). Readers are invited to keep current with advances in various disciplines, gain insight into fields other than their own, and refresh their understanding of core concepts in cell & molecular biology. Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This eBook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the eBooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each eBook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material.Published titles (for future titles please see the website, www.morganclaypool.com/page/lifesci) ABSTRACTThe major purpose of this book is to review the evidence supporting the concept that intrinsic cell survival programs can be activated by a variety of mildly noxious stimuli or pharmacologic agents to confer protection against the deleterious effects of ischemia/reperfusion (I/R). We begin with a discussion of the concept of hormesis (a term used most extensively in the toxicologic literature which refers to biphasic cellular responses that depend on concentration or intensity of a stimulus), review the seminal studies that led to the discovery of the cardioprotective effects of ischemic preconditioning, and outline its therapeutic potential (Chapter 1). This is followed ...

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Ethanol for cardiac ischemia: the role of protein kinase c

Cited by 11 publications

References 129 publications

Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms

Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms

Selective Phosphorylation Inhibitor of Delta Protein Kinase C–Pyruvate Dehydrogenase Kinase Protein–Protein Interactions: Application for Myocardial Injury in Vivo

Cell Survival Programs and Ischemia /Reperfusion: Hormesis, Preconditioning, and Cardioprotection

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