Abstract:
:Recent reports indicate that elevating DNA glycosylase/AP lyase repair enzyme activity offers marked cytoprotection in cultured cells and a variety of injury models. In this study, we measured the effect of EndoIII, a fusion protein construct that traffics Endonuclease III, a DNA glycosylase/AP lyase, to the mitochondria, on infarct size in a rat model of myocardial ischemia/reperfusion. Open-chest, anesthetized rats were subjected to 30 min of occlusion of a coronary artery followed by 2 h of reperfusion. An intravenous bolus of EndoIII, 8 mg/kg, just prior to reperfusion reduced infarct size from 43.8 ± 1.4% of the risk zone in control animals to 24.0 ± 1.3% with no detectable hemodynamic effect. Neither EndoIII's vehicle nor an enzymatically inactive EndoIII mutant (K120Q) offered any protection. The magnitude of EndoIII's protection was comparable to that seen with the platelet aggregation inhibitor cangrelor (25.0 ± 1.8% infarction of risk zone). Because loading with a P2Y12 receptor blocker to inhibit platelets is currently the standard of care for treatment of acute myocardial infarction, we tested whether EndoIII could further reduce infarct size in rats treated with a maximally protective dose of cangrelor. The combination reduced infarct size to 15.1 ± 0.9% which was significantly smaller than that seen with either cangrelor or EndoIII alone. Protection from cangrelor but not EndoIII was abrogated by pharmacologic blockade of phosphatidylinositol-3 kinase or adenosine receptors indicating differing cellular mechanisms. We hypothesized that EndoIII protected the heart from spreading necrosis by preventing the release of proinflammatory fragments of mitochondrial DNA (mtDNA) into the heart tissue. In support of this hypothesis, an intravenous bolus at reperfusion of deoxyribonuclease I (DNase I) which should degrade any DNA fragments escaping into the extracellular space was as protective as EndoIII. Furthermore, the combination of EndoIII and DNase I produced additive protection. While EndoIII would maintain mitochondrial integrity in many of the ischemic cardiomyocytes, DNase I would further prevent mtDNA released from those cells that EndoIII could not save from propagating further necrosis. Thus, our mtDNA hypothesis would predict additive protection. Finally to demonstrate the toxicity of mtDNA, isolated hearts were subjected to 15 min of global ischemia. Infarct size doubled when the coronary vasculature was filled with mtDNA fragments during the period of global ischemia. To our knowledge, EndoIII and DNase are the first agents that can both be given at reperfusion and add to the protection of a P2Y12 blocker, and thus should be effective in today's patient with acute myocardial infarction.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Yang XM,Cui L,White J,Kuck J,Ruchko MV,Wilson GL,Alexeyev M,Gillespie MN,Downey JM,Cohen MVdoi
10.1007/s00395-014-0459-0subject
Has Abstractpub_date
2015-03-01 00:00:00pages
3issue
2eissn
0300-8428issn
1435-1803journal_volume
110pub_type
杂志文章abstract::To understand the effect of transcription regulation in modulating cardiac aging, we sought to study the role of serum response factor (SRF), a key transcription factor in the heart that is normally increased with senescence and also in congestive heart failure. A Tet-Off gene expression system was used for cardiac-sp...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-006-0634-z
更新日期:2007-05-01 00:00:00
abstract::The aim of the present study was to evaluate the expression of hedgehog (Hh) signaling molecules and the chemotactic activity of Sonic hedgehog (Shh) in monocytes from control (CTR) and diabetic patients with or without coronary artery disease (CAD). Previously several studies demonstrated that exogenous administratio...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-009-0047-x
更新日期:2010-01-01 00:00:00
abstract::Ischaemic preconditioning has not been demonstrated to reduce infarct size following global ischaemia in murine myocardium. Eighteen mouse hearts were isolated, perfused in the Langendorff mode, and randomised to control or preconditioning groups. Preconditioned hearts received four periods of five minutes global isch...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s003950050106
更新日期:1998-10-01 00:00:00
abstract::We investigated whether preconditioning could protect several cultured cell lines, to determine whether the protection is specific for cells derived from different myogenic and non-myogenic sources. Ischemia was simulated by centrifugation of cells into a pellet, and cell viability was determined by hypotonic trypan b...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF00788726
更新日期:1996-11-01 00:00:00
abstract::We describe diastolic properties of the myocardium in terms of stress-strain relations. In a mathematical analysis, the equation sigma = alpha(e beta.epsilon-1) of the stress-strain curve can be changed by an increase in the exponent beta or the multiplicative constant alpha. It can be experimentally shown that in hyp...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/978-3-662-11289-2_26
更新日期:1987-01-01 00:00:00
abstract::An adult rat heart myocyte preparation was used to study the uptake and metabolism of the 1-14C-labelled fatty acids decanoate, laurate, myristate, and palmitate. Metabolism was saturable, but free fatty acid accumulation was not. Use of metabolic inhibitors indicated that metabolism and not uptake was rate limiting a...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::Hearts preconditioned by brief ischemia are characterized by a reduced rate of cellular purine metabolite production during subsequent prolonged ischemia; the purpose of this study was to determine if transient exogenous adenosine pretreatment can mimic this phenomenon. The accumulation of interstitial fluid (ISF) pur...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF00796210
更新日期:1997-12-01 00:00:00
abstract::The available data clearly suggest large alterations in myocardial eicosanoid generation during myocardial ischaemia and demonstrate important actions of eicosanoids on myocardial function during ischaemic conditions. These actions include direct effects on the injured myocardium as well as influences on other target ...
journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
doi:10.1007/978-3-662-08390-1_27
更新日期:1987-01-01 00:00:00
abstract::The ability of the rhesus monkey to form coronary collaterals was tested in ten animals. Ameroid constrictors were implanted on the left circumflex coronary artery and allowed to remain for 12 weeks. One animal died of an acute myocardial infarction nine days after surgery; the remaining animals survived without clini...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01906462
更新日期:1983-09-01 00:00:00
abstract::The effect of 0.1 mg/kg Verapamil on the extent of the ischemic area following ligation of a branch of the left descending coronary artery was studied in anesthetized open chest dogs. The sum of the ST-segment elevation during the entire period of occlusion in the epicardial ECG was 15 mV in control infarction compare...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01905620
更新日期:1975-03-01 00:00:00
abstract::Delta-opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role of kappa-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2 h reperfusion. PC (2 cycles 5 min global ischemia) substantially r...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s003950050001
更新日期:2000-02-01 00:00:00
abstract::In dog myocardium, the changes in the levels of creatine phosphate, inorganic phosphate, ATP, ADP, AMP, adenosine and inosine with 8 min of ischemia and subsequent reperfusion for 2, 4, 8, 16 and 32 min have been followed. Creatine phosphate and inorganic phosphate recovered completely within a few minutes as did the ...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01907461
更新日期:1986-07-01 00:00:00
abstract::A computer model is presented for simulation of the spread of activation and repolarization in ventricular myocardium. The program calculating the activation sequence is based on an algorithm similar to Huygen's principle of constructing wavefronts. Physiological parameters of the heart, such as areas of early activat...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF02650875
更新日期:1989-07-01 00:00:00
abstract::Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with a strong genetic component. Molecular pathways involving the homeodomain transcription factor Shox2 control the development and function of the cardiac conduction system in mouse and zebrafish. Here we report the analysis of human SHOX2 as a potent...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-016-0557-2
更新日期:2016-05-01 00:00:00
abstract::We chronically implanted hygroscopic occluders around the left circumflex coronary artery in 49 anesthetized young male domestic pigs and we studied the development of a collateral circulation at 4, 8, 12, and 26 weeks after implantation. At these time intervals groups of animals were again anesthetized, the hearts we...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01908204
更新日期:1989-09-01 00:00:00
abstract::The role of the cardiac current Ik1 in arrhythmogenesis remains highly controversal. To gain further insights into the mechanisms of IK1 involvement in cardiac excitability, we studied the susceptibility of transgenic mice with altered IK1 to arrhythmia during various pharmacological and physiological challenges. Arrh...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-007-0659-y
更新日期:2007-09-01 00:00:00
abstract::K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca(2+)](o)). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca(2+) rel...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-011-0218-4
更新日期:2011-11-01 00:00:00
abstract::We hypothesized that nandrolone (ND)-abuse induces cardiac hypertrophy, increases myocardial susceptibility to ischemia/reperfusion (I/R) injury, and reduces responsiveness to postconditioning (PostC) cardioprotection. Wistar-rats were ND treated for 2 weeks (short_ND) or 10 weeks (long_ND). Vehicle-treated rats serve...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-010-0143-y
更新日期:2011-05-01 00:00:00
abstract::Recent studies demonstrated that NADPH oxidase 2 (NOX2) expression in myocardium after ischemia-reperfusion (IR) is significantly upregulated. However, the underlying mechanisms remain unknown. This study aims to determine if nuclear cardiac myosin light chain 2 (MYL2), a well-known regulatory subunit of myosin, funct...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-015-0494-5
更新日期:2015-01-01 00:00:00
abstract::In the human ventricle two isoforms of the phosphorylatable myosin light chain (MPLC) are expressed. These two forms are designated with increasing acidity as LC-2 and LC-2*. In the normal human heart the relation between LC-2/LC-2*-expression is 70/30, suggesting the existence of three different myosin isoenzymes (MP...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/978-3-642-72474-9_11
更新日期:1992-01-01 00:00:00
abstract::Atrial fibrosis is important for the pathogenesis of atrial fibrillation (AF) but the underlying signal transduction is incompletely understood. We therefore studied the role of microRNA-21 (miR-21) and its downstream target Sprouty 1 (Spry1) during atrial fibrillation. Left atria (LA) from patients with AF showed a 2...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-012-0278-0
更新日期:2012-09-01 00:00:00
abstract:AIMS:There is a need for better identification of patients at high risk for malignant arrhythmias who would benefit from implantable cardioverter defibrillators (ICD). The purpose of this study was to assess whether the C825T polymorphism in the G-protein beta3 subunit gene, GNB3, might serve as a genetic marker for re...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-006-0600-9
更新日期:2006-09-01 00:00:00
abstract::In the newborn several situations of hyperinsulinism can be associated with myocardial hypertrophy and increased contractility. Insulin and the insulin-like growth factors (IGF) are derived from a common ancestral molecule. Insulin exerts mainly metabolic action, whereas the IGFs promote cell multiplication and differ...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01906959
更新日期:1988-11-01 00:00:00
abstract::This paper reviews the recent data concerning the force-frequency relations in experimental animals with heart failure. After a brief overview of the nature of these relations, which are induced by 2 opposite phenomena, the potentiation of force of contraction by heart rate and the restitution process, the paper revie...
journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
doi:10.1007/s003950050212
更新日期:1998-01-01 00:00:00
abstract::We tested the hypothesis that in isolated cardiac myocytes, the negative functional effects of cyclic GMP would be blunted when the level of cyclic AMP was increased and that this interaction would be altered in renal hypertensive (One-Kidney-One-Clip, 1K1C) cardiac hypertrophic rabbits. Using isolated control and 1K1...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s003950170075
更新日期:2001-02-01 00:00:00
abstract::Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that CD4-positive lymphocytes express the nuclear transcription factors Liver-X-Receptor (LXR) alpha and beta with an effect of LXR activators on TH1-cytokine release from these cells. However, the role ...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/s00395-010-0092-5
更新日期:2010-07-01 00:00:00
abstract::Implicit in attempts to characterize and purify biologically active factors is the premise that the bioassay system employed will show a progressive increase in the response as the concentration of the responsible factor increases. We employed the hamster cheek pouch to assay the neovascularization potential of growth...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF01907406
更新日期:1986-05-01 00:00:00
abstract::This study was aimed to assess the relationship among the voltage-dependent processes underlying the excitation-contraction coupling, viz. force restitution (FR), transmembrane Ca fluxes and Ca release. The experiments (n = 22) were performed on voltage-clamped dog trabeculae in which force and slow inward current wer...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/BF00795054
更新日期:1992-09-01 00:00:00
abstract::At 36 degrees C and 2 mM [Ca2+]o, single guinea-pig ventricular myocytes were voltage clamped with patch electrodes. When paired pulsing had potentiated the contraction to the maximum, the cells were shock-frozen for electron probe microanalysis (EPMA). Shock-freezing was timed at the end of diastole (-80 mV) or at di...
journal_title:Basic research in cardiology
pub_type: 杂志文章
doi:10.1007/978-3-662-30769-4_9
更新日期:1991-01-01 00:00:00
abstract::Dopexamine is a newly developed sympathetic catecholamine which combines dopaminergic (DA-1) and beta 2-adrenergic agonist activity with only minor beta 1-adrenergic action. Thereby, this compound exerts systemic and preferential renal vasodilation, causing afterload reduction, increases in cardiac output, and improve...
journal_title:Basic research in cardiology
pub_type: 杂志文章,评审
doi:10.1007/BF02650357
更新日期:1989-01-01 00:00:00