Transcription inhibitor actinomycin-D abolishes the cardioprotective effect of ischemic reconditioning

Strohm, Claudia; Barančı́k, Miroslav; Bruehl, Marie-Luise von; Strniskova, Monika; Ullmann, Claudia; Zimmermann, René; Schäper, Wolfgang

doi:10.1016/s0008-6363(02)00453-4

Cited by 33 publications

(26 citation statements)

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“…Activation of mito K ATP channels and protein translation also play a role in improvement of postischemic function. These findings, together with those of other recent studies Matsuda et al, 2000;Matsuyama et al, 2000;Strohm et al, 2002], indicate that acute responses to ischemia and cardioprotective stimuli do involve transcriptional and translational elements, and are not solely mediated via posttranslational processes.…”

Section: Discussionsupporting

confidence: 78%

“…Indeed, Heads et al [1995] concluded that changes in HSP60 expression were not important in the early protective effect of adenosine-mediated preconditioning, and Sommerschild et al [1999] Responses are shown for untreated hearts (n=8), and hearts treated with 50 mM adenosine (Ado, n=10), 10 mM CHX (n=8), 20 mM Act-D (n=8), 1.5 mM a-amanitin (n=9), 50 mM adenosine+10 mM CHX (n=8), 50 mM adenosine+20 mM Act-D (n=8), or 50 mM adenosine+1.5 mM a-amanitin (n=9 (n=8), and hearts treated with 50 mM adenosine (n=10), 100 mM 5-HD (n=9), 50 mM adenosine +100 mM 5-HD (n=8), 50 mM adenosine +100 mM 5-HD+10 mM CHX (n=8), or 50 mM adenosine +100 mM 5-HD+20 mM Act-D (n=8 decline rather than improvement in function with adenosine transport inhibition in their model. Nonetheless, several recent studies support a role for acute transcriptional or translational events in cardioprotective responses Matsuda et al, 2000;Matsuyama et al, 2000;Strohm et al, 2002], raising the possibility that transcription and translation may be involved in protective responses to adenosine. To reduce the potential contribution of protein synthesis to the adenosine response, we treated hearts with CHX, which specifically and potently blocks the translocation reaction at eukaryotic ribosomes [Yeh and Shils, 1969].…”

Section: Discussionmentioning

confidence: 99%

“…The acute protective effects of adenosine have generally been assumed to involve posttranslational mechanisms rather than changes in gene transcription and/or protein synthesis [Thornton et al, 1990;Meldrum et al, 1997;Baxter and Ferdinandy, 2001]. However, there is some support for rapid changes in myocardial gene expression during acute ischemic [Heads et al, 1995;Lyn et al, 2000;Kitakaze et al, 2001] or protective stimuli [Das et al, 1993;Deindl and Schaper, 1998;Maulik et al, 1999;Matsuda et al, 2000], and recent research indicates de novo protein synthesis and/or gene transcription are essential in acute protection with preconditioning Matsuyama et al, 2000;Strohm et al, 2002]. There is evidence that adenosine receptors can modify gene expression in noncardiac tissues [Chae and Kim, 1997;Harii et al, 1999], and mixed support for adenosine-dependent modulation of postischemic gene expression [Heads et al, 1995;Sommerschild et al, 1999].…”

Section: Introductionmentioning

confidence: 99%

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Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Headrick

Peart

Holmgren

et al. 2003

Drug Development Research

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Adenosine protects against myocardial ischemic injury via poorly defined mechanisms. We examined effects of inhibition of gene transcription, mRNA translation, and mitochondrial K ATP channels on cardioprotective effects of adenosine in mouse hearts subjected to 20-min ischemia. Adenosine treatment reduced postischemic lactate dehydrogenase efflux (indicating necrosis) from 2472 to 971 IU/g, and postischemic diastolic contracture from 2172 to 572 mm Hg, and enhanced postischemic ventricular pressure development from 7273 to 13574 mm Hg. The antinecrotic response was reduced E50% by inhibition of protein translation (10 mM cycloheximide, CHX), unaltered by inhibition of transcription (20 mM actinomycin D, Act-D), and abrogated by mitochondrial K ATP channel inhibition (100 mM 5-hydroxydecanoate, 5-HD). In contrast, protection against contractile dysfunction was reduced but not eliminated by CHX, Act-D, and 5-HD, and inhibitory effects CHX and Act-D were not additive with those of 5-HD, supporting a common mechanistic path. Inhibitory effects of Act-D were mimicked by 1.5 mM a-amanitin. These data provide evidence that adenosine limits necrosis in a mito K ATP channel-dependent manner involving protein translation. The translational component is not dependent upon mRNA transcription. Adenosine also substantially reduces contractile dysfunction via a pathway involving mitochondrial K ATP channel activation, protein translation, and mRNA transcription. Protection independent of this path was also evident. Thus, distinct signaling pathways appear to be involved in adenosine-mediated protection against postischemic necrosis and contractile dysfunction. Drug Dev. Res. 58:454-460, 2003.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Headrick

Peart

Holmgren

et al. 2003

Drug Development Research

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“…Interestingly, Claudin has not been looked at in terms of cardioprotection nor has CASPR3 nor CDC42-binding protein kinase beta. Nonetheless, S100 has been looked at in cardioprotection as a factor that assists mediation of ischemic preconditioning [17]. This observation is very much consistent with my prosurvival model [6].…”

Section: Introductionsupporting

confidence: 65%

Harvesting the Benefits of Understanding Cancer with the Use of ?Shuttle? Era Technology- Cellular Survival Strategies and Tissue Engineering Via Grafting of Genetically Immortalized Autologous Cells

2012

JBABM

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This review aims to focus on several of the advantages that an improved understanding of the biology of cancer may offer medicine. Following in the wake of my recent review demonstrating the close molecular mechanistic relationship between heart survival mechanisms and those of cancer under environmental challenge I examine how cancer can provide survival answers for tissues under physiological challenge. I continue the basis of this discussion with the argument that cancer can offer clues as to how to better develop reliable and sound strategies for tissue/organ regeneration. For a number of years the concept with the use of stem cells to enable tissue and/ or organ regeneration has gained attention. Indeed, recently, tooth buds have been regenerated from mouse stem cells allowing complete tooth regeneration in vivo. In this review, the focus is on alternative means for tissue/ organ regeneration by harnessing the all-sort-after property of cellular immortality that cancer possesses in its armamentarium. Literature is presented to demonstrate the utility and practicality of immortal genetic modification of autologous post-mitotic and senescent cells for reimplantation. This process may be of practical value in numerous medical situations from degenerative neurological diseases, wound healing, hair follicle replacement and auditory repair to aiding functional repair of cardiac disease to name but a few. The rational benefits of this technique are presented over stem cell technologies and potential technical obstacles are outlined that may need to be overcome. Novel technologies derived from the use of shuttle expression vectors are outlined here to screen for therapyresistance genes in cancer. These methods may be further enhanced and developed to allow delineation of genes involved in preventing cellular senescence whilst not transforming cells to a cancerous phenotype. These genes can subsequently be used in genetic modification of autologously harvested cells for re-implantation to enable tissue and/or organ regeneration.

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“…However, acute changes in gene expression occur during ischemia-reperfusion (120,183) and with protective stimuli (46, 51, 198), and there is support for roles for de novo protein synthesis and/or gene transcription in acute protection with preconditioning (199,241,268). Several studies provide intriguing, if not compelling, support for a transcriptional component in acute adenosinergic protection (120,266).…”

Section: Are Acute Effects Of Adenosine Receptor Activation Entirely mentioning

confidence: 99%

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

Headrick

Hack

Ashton

2003

American Journal of Physiology-Heart and Circulatory Physiology

150

164

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. Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 285: H1797-H1818, 2003; 10.1152/ajpheart.00407. 2003.-Cells of the cardiovascular system generate and release purine nucleoside adenosine in increasing quantities when constituent cells are "stressed" or subjected to injurious stimuli. This increased adenosine can interact with surface receptors in myocardial, vascular, fibroblast, and inflammatory cells to modulate cellular function and phenotype. Additionally, adenosine is rapidly reincorporated back into 5Ј-AMP to maintain the adenine nucleotide pool. Via these receptor-dependent and independent (metabolic) paths, adenosine can substantially modify the acute response to ischemic insult, in addition to generating a more sustained ischemia-tolerant phenotype (preconditioning). However, the molecular basis for acute adenosinergic cardioprotection remains incompletely understood and may well differ from more widely studied preconditioning. Here we review current knowledge and some controversies regarding acute cardioprotection via adenosine and adenosine receptor activation.adenosine; adenosine receptor activation; ischemia; reperfusion injury THE HEART possesses its own intrinsic protective responses, including the adenosine receptor system, which enhance resistance to ischemic insult. An understanding of the mechanisms involved in these responses not only informs us of how the heart reacts to injurious stimuli, but may provide avenues for developing novel protective strategies applicable in the setting of ischemia-reperfusion. The purine nucleoside adenosine was attributed with cardioregulatory functions almost 75 years ago (64), and since then has emerged as a crucially important control substance in essentially every tissue of the body. In the heart adenosine not only plays a role in regulating growth and differentiation, angiogenesis, coronary blood flow, cardiac conduction and heart rate, substrate metabolism, and sensitivity to adrenergic stimulation (23,67,68,73,74,260,271,283), but may play a role as an endogenous determinant of ischemic tolerance (189,225,245,259,311,312,318). From a therapeutic viewpoint, adenosine-based therapies protect against ischemic injury in a variety of animal models (72,177,208,265,288) and in human cardiac tissue (34, 36, 37,240,296). However, much remains unclear regarding the roles and mechanisms of action of adenosine in producing acute protection against ischemia and reperfusion. Generation of Endogenous Adenosine During InsultEndogenous adenosine levels increase rapidly with ischemic insult (104,109,285,286) to mediate a retaliatory response. This protective pool of adenosine can be formed via dephosphorylation of 5Ј-AMP by intra-and extracellular 5Ј-nucleotidases and from S-adenosylhomocysteine (SAH) via SAH hydrolase. Extracellular adenosine is rapidly taken into cells via a facilitative transporter (131). Within cells it is either deaminated by adenosine deaminase or rephosphorylated to 5Ј-AMP via adenosine kinase. O...

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Transcription inhibitor actinomycin-D abolishes the cardioprotective effect of ischemic reconditioning

Cited by 33 publications

References 65 publications

Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Evidence of tanscriptional and tanslational components in anti‐ischemic effects of adenosine

Harvesting the Benefits of Understanding Cancer with the Use of ?Shuttle? Era Technology- Cellular Survival Strategies and Tissue Engineering Via Grafting of Genetically Immortalized Autologous Cells

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

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