Ischemic acidosis causes apoptosis in coronary endothelial cells through activation of caspase-12.

OBJECTIVE Myocardial ischemia has been shown to induce apoptosis of endothelial cells (EC). However, the mechanism of this endothelial injury is still poorly understood. To analyse the signaling pathway of ischemia-induced EC apoptosis was the aim of the present study. METHODS The primary culture of rat coronary EC was exposed to simulated ischemia (glucose-free anoxia at pH(o) 6.4). Apoptosis was defined by staining of nuclei with Hoechst-33342 and TUNEL. Cytosolic Ca2+ and pH were measured with Fura-2 and BCECF, respectively. RESULTS Apoptosis (29.2+/-1.7% of cells) induced by exposure to simulated ischemia for 2 h was accompanied by cytosolic Ca2+ overload (1090+/-52 nmol/l) and acidosis (pHi = 6.52+/-0.13). Simulated ischemia had no significant effect on caspase-8 cleavage, but induced cleavage of caspase-3 and caspase-12 and led to a slight release of cytochrome C. Prevention of cytosolic acidosis (anoxia at pH(o) 7.4) had no effect on cytochrome C release, but significantly reduced apoptosis, attenuated cytosolic Ca2+ overload, and prevented cleavage of caspase-12. A similar effect was achieved by inhibition of Ca2+ release channels in the endoplasmic reticulum with ryanodine and xestospongin C. Knock-down of caspase-12 with small interfering RNA suppressed caspase-3 activation and reduced apoptotic cell number by about 70%. CONCLUSION Acidosis, rather than anoxia, is an important trigger of apoptosis in EC under simulated ischemia. The main pathway of the simulated ischemia-induced apoptosis consists of the Ca2+ leak from the ER followed by activation of caspase-12 and caspase-3.

• Publication year

  2007

• Venue

  Cardiovascular Research

• Publication date

  2007-01-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/J.CARDIORES.2006.09.018PMID 17083921
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Circulating CD31+/Annexin V+ Apoptotic Microparticles Correlate With Coronary Endothelial Function in Patients With Coronary Artery Disease

  2006cited by this paper
• Selective role for superoxide in InsP3 receptor–mediated mitochondrial dysfunction and endothelial apoptosis

  2005cited by this paper
• Amiloride potentiates TRAIL-induced tumor cell apoptosis by intracellular acidification-dependent Akt inactivation.

  2005cited by this paper
• Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells.

  2005cited by this paper
• Induction of Endoplasmic Reticulum-induced Stress Genes in Panc-1 Pancreatic Cancer Cells Is Dependent on Sp Proteins*

  2005cited by this paper
• Cyclic AMP alleviates endoplasmic stress and programmed cell death induced by lipopolysaccharides in human endothelial cells

  2005cited by this paper
• Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

  2005cited by this paper
• Acidosis-induced apoptosis in human and porcine heart.

  2004cited by this paper
• Nitric oxide: a signaling molecule against mitochondrial permeability transition- and pH-dependent cell death after reperfusion.

  2004cited by this paper
• Role of the permeability transition pore in cytochrome C release from mitochondria during ischemia-reperfusion in rat liver.

  2004cited by this paper
• Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP

  2004cited by this paper
• Acidification reduces mitochondrial calcium uptake in rat cardiac mitochondria.

  2004cited by this paper
• Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death

  2004cited by this paper
• Induction of neuronal death by ER stress in Alzheimer's disease.

  2004cited by this paper
• Role of Caspases in Ox-LDL–Induced Apoptotic Cascade in Human Coronary Artery Endothelial Cells

  2004cited by this paper
• Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia.

  2003cited by this paper
• Regulation of apoptosis by endoplasmic reticulum pathways

  2003influential reference
• Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

  2003influential reference
• Inhibition of apoptosis in pulmonary endothelial cells by altered pH, mitochondrial function, and ATP supply.

  2002cited by this paper
• Different Signaling Pathways Induce Apoptosis in Endothelial Cells and Cardiac Myocytes During Ischemia/Reperfusion Injury

  2002cited by this paper
• Human caspase 12 has acquired deleterious mutations.

  2002cited by this paper
• Caspase-12 processing and fragment translocation into nuclei of tunicamycin-treated cells

  2002cited by this paper
• An Endoplasmic Reticulum Stress-specific Caspase Cascade in Apoptosis

  2002cited by this paper
• Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression.

  2000cited by this paper
• Mechanism of Ca(2+) overload in endothelial cells exposed to simulated ischemia.

  2000cited by this paper
• Hypoxia-activated apoptosis of cardiac myocytes requires reoxygenation or a pH shift and is independent of p53.

  1999influential reference
• Cardiac microvascular endothelial cells express alpha-smooth muscle actin and show low NOS III activity.

  1999cited by this paper
• Cardiac microvascular endothelial cells express α-smooth muscle actin and show low NOS III activity.

  1999cited by this paper
• Apoptotic vascular endothelial cells become procoagulant.

  1997cited by this paper
• A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide).

  1997cited by this paper
• Metabolic adaptation during a sequence of no-flow and low-flow ischemia. A possible trigger for hibernation.

  1996cited by this paper
• Cell acidification in apoptosis: granulocyte colony-stimulating factor delays programmed cell death in neutrophils by up-regulating the vacuolar H(+)-ATPase.

  1995cited by this paper
• A functional ryanodine-sensitive intracellular Ca2+ store is present in vascular endothelial cells.

  1994cited by this paper
• Identification of deoxyribonuclease II as an endonuclease involved in apoptosis.

  1993cited by this paper
• Anti-ryanodine receptor antibody binding sites in vascular and endocardial endothelium.

  1993cited by this paper
• Microvascular Endothelial Cells from Heart

  1990cited by this paper

• PMAIP1 mediates endoplasmic reticulum stress in human dental pulp stem cells during pulpitis pathogenesis

  2025cites this paper
• Acidosis induces autophagic cell death through ASIC1-mediated Akt/mTOR signaling in HT22 neurons.

  2025cites this paper
• Effect of intermittent extracellular low-pH environment on human umbilical vein endothelial cell activity

  2025cites this paper
• Myocardial Ischemia–Reperfusion Injury: Unraveling Pathophysiology, Clinical Manifestations, and Emerging Prevention Strategies

  2024cites this paper
• Cytochrome c electrochemical detection utilizing molecularly imprinted poly(3, 4-ethylenedioxythiophene) on a disposable screen printed carbon electrode.

  2024cites this paper
• Low pH Attenuates Apoptosis by Suppressing the Volume-Sensitive Outwardly Rectifying (VSOR) Chloride Current in Chondrocytes

  2022cites this paper
• LASS2 overexpression enhances early apoptosis of lung cancer cells through the caspase‑dependent pathway.

  2022cites this paper
• Mesenchymal stem cell-derived conditioned medium protects vascular grafts of brain-dead rats against in vitro ischemia/reperfusion injury

  2021cites this paper
• The gut-cardiovascular connection: new era for cardiovascular therapy

  2021cites this paper
• Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

  2021cites this paper
• Failing Heart Transplants and Rejection—A Cellular Perspective

  2021cites this paper
• Trimethylamine-N-oxide-stimulated hepatocyte-derived exosomes promote inflammation and endothelial dysfunction through nuclear factor-kappa B signaling

  2021cites this paper
• The antagonistic effect of magnesium hydroxide particles on vascular endothelial activation induced by acidic PLGA degradation products.

  2020cites this paper
• Acid-sensing ion channels: linking extracellular acidification with atherosclerosis.

  2019cites this paper
• Responses of Endothelial Cells Towards Ischemic Conditioning Following Acute Myocardial Infarction.

  2018cites this paper
• The Caspase Cascade During Hibernation in the Golden-~Mantled Ground Squirrel, Spermophilus lateralis

  2018cites this paper
• Detection of ischemic changes in the vascular endothelial cell layer by using microelectrochemical impedance spectroscopy.

  2018cites this paper
• Erratum to: Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside

  2017cites this paper
• Monocarboxylate Transporter‐1 Mediates the Protective Effects of Neutral‐pH Bicarbonate/Lactate‐Buffered Peritoneal Dialysis Fluid on Cell Viability and Apoptosis

  2017cites this paper
• Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells

  2017cites this paper
• Mise au point sur les conséquences hémodynamiques de l’acidose lactique dans les états de choc Hemodynamic Consequences of Severe Lactic Acidosis in Shock States

  2017influential citation
• Mise au point sur les conséquences hémodynamiques de l’acidose lactique dans les états de choc

  2017cites this paper
• Acidic stress induces apoptosis and inhibits angiogenesis in human bone marrow-derived endothelial progenitor cells

  2017cites this paper
• Cellular and molecular mechanisms of endothelial ischemia/reperfusion injury: perspectives and implications for postischemic myocardial protection.

  2016cites this paper
• Impacts hémodynamique et inflammatoire de la modulation de la fréquence cardiaque dans le choc septique

  2016influential citation
• Biocompatibility of neutral bicarbonate-buffered peritoneal dialysis solution

  2016cites this paper
• Early Administration of Glutamine Protects Cardiomyocytes from Post-Cardiac Arrest Acidosis

  2016cites this paper
• Vascular Endothelial Function in Ischemia/Reperfusion Injury: Pathophysiological Mechanisms and Clinical Implications for Postischemic Myocardial Protection

  2015cites this paper
• Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside

  2015cites this paper
• Coronary flow reserve is associated with tissue ischemia and is an additive predictor of intensive care unit mortality to traditional risk scores in septic shock.

  2014cites this paper
• Role of soluble adenylyl cyclase in cell death and growth.

  2014cites this paper
• Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

  2014cites this paper
• Glucose-Regulated Protein 78 (Grp78) Confers Chemoresistance to Tumor Endothelial Cells under Acidic Stress

  2014cites this paper
• Influence of growth factors and cytokines on angiogenic function of endothelial progenitor cells: a review of in vitro human studies

  2014cites this paper
• Molecular and cellular mechanisms of vomeronasal signaling in mammals

  2013cites this paper
• Nanomaterial-based electrochemical biosensors for cytochrome c using cytochrome c reductase.

  2013cites this paper
• New concepts of endoplasmic reticulum function in the heart: programmed to conserve.

  2013cites this paper
• Regulation of inflammation by extracellular acidification and proton-sensing GPCRs.

  2013cites this paper
• Role of SLMAP in Endoplasmic Reticulum Stress and Unfolded Protein Response

  2013cites this paper
• Phosphonated trityl probes for concurrent in vivo tissue oxygen and pH monitoring using electron paramagnetic resonance-based techniques.

  2013cites this paper
• Cardioprotection afforded by targeting guanylyl cyclase during early reperfusion

  2012cites this paper
• Use of RNA interference to minimize ischemia reperfusion injury.

  2012cites this paper
• Acidic preconditioning protects against ischemia-induced brain injury.

  2012cites this paper
• Calcium-activated Potassium Channels in Vasculature in Response to Ischemia-Reperfusion

  2012cites this paper
• Preconditioning with hypercapnic acidosis: hope for the ischemic brain.

  2012cites this paper
• Protective effect of erythropoietin on myocardial infarction in rats by inhibition of caspase-12 expression.

  2011cites this paper
• The low viability of human CD34+ cells under acidic conditions is improved by exposure to thrombopoietin, stem cell factor, interleukin‐3, or increased cyclic adenosine monophosphate levels

  2011cites this paper
• SLC4A7 sodium bicarbonate co-transporter controls mitochondrial apoptosis in ischaemic coronary endothelial cells.

  2011influential citation
• Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells*

  2009cites this paper
• Lentiviral-mediated overexpression of Bcl-xL protects primary endothelial cells from ischemia/reperfusion injury-induced apoptosis.

  2009cites this paper
• Cytosolic Ca2+ Oscillations in Human Cerebrovascular Endothelial Cells after Subarachnoid Hemorrhage

  2009cites this paper
• A proton-activated, outwardly rectifying chloride channel in human umbilical vein endothelial cells.

  2008cites this paper
• Nonischemic myocardial acidosis adversely affects microvascular and myocardial function and triggers apoptosis during cardioplegia.

  2008cites this paper
• Acidic preconditioning protects endothelial cells against apoptosis through p38- and Akt-dependent Bcl-xL overexpression

  2008cites this paper
• 7-Ketocholesterol activates caspases-3/7, -8, and -12 in human microvascular endothelial cells in vitro.

  2008cites this paper
• Cardiomyocyte death and renewal in the normal and diseased heart.

  2008cites this paper
• Acidic reoxygenation protects against endothelial dysfunction in rat aortic rings submitted to simulated ischemia.

  2008cites this paper
• Acidic pre-conditioning suppresses apoptosis and increases expression of Bcl-xL in coronary endothelial cells under simulated ischaemia

  2007cites this paper
• Importance of bicarbonate transport for ischaemia-induced apoptosis of coronary endothelial cells

  2007influential citation