S100A8 and S100A9 Mediate Endotoxin-Induced Cardiomyocyte Dysfunction via the Receptor for Advanced Glycation End Products

Cardiovascular dysfunction as a result of sepsis is the leading cause of death in the critically ill. Cardiomyocytes respond to infectious pathogens with a Toll-like receptor–initiated proinflammatory response in conjunction with a decrease in contractility, although the downstream events linking Toll-like receptor activation and reduced cardiac contractility remain to be elucidated. Using microarray analysis of cardiac tissue exposed to systemic lipopolysaccharide (LPS), we discovered that 2 small calcium-regulating proteins (S100A8 and S100A9) are highly upregulated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and live mice were exposed to LPS, whereas beating HL-1 cells had S100A8 and S100A9 overexpressed and their calcium flux quantified. Using in vivo microbubble technology, we delivered S100A8 and S100A9 to normal mouse hearts; using the same technology, we inhibited S100A9 production in mouse hearts and subsequently exposed them to LPS. Coimmunoprecipitation of S100A8 and S100A9 identified interaction with RAGE (the receptor for advanced glycation end products), the cardiac function and postreceptor signaling of which were investigated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and whole hearts exposed to LPS have large increases in S100A8 and S100A9. Cardiac overexpression of S100A8 and S100A9 led to a RAGE-dependent decrease in calcium flux and, in the intact mouse, to a decreased cardiac ejection fraction, whereas knockdown of S100A9 attenuated LPS-induced cardiac dysfunction. Cardiomyocytes exposed to LPS express S100A8 and S100A9, leading to a RAGE-mediated decrease in cardiomyocyte contractility. This finding provides a novel mechanistic link between circulating pathogen-associated molecular products and subsequent cardiac dysfunction.

[1]  H. Katus,et al.  Impact of microbubbles on shock wave-mediated DNA uptake in cells in vitro. , 2007, Ultrasound in medicine & biology.

[2]  H. Katus,et al.  Targeting the heart with gene therapy-optimized gene delivery methods. , 2007, Cardiovascular research.

[3]  Godfrey L. Smith,et al.  S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes. , 2007, Cell calcium.

[4]  K. Herold,et al.  Blockade of RAGE Suppresses Alloimmune Reactions In Vitro and Delays Allograft Rejection in Murine Heart Transplantation , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[5]  K. Walley,et al.  Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. , 2006, Cardiovascular research.

[6]  A. Remppis,et al.  S100A1 gene transfer in myocardium. , 2006, European journal of medical research.

[7]  E. Dinjus,et al.  The potential of a new stable ultrasound contrast agent for site-specific targeting. An in vitro experiment. , 2006, Ultrasound in medicine & biology.

[8]  M. Völkers,et al.  Cardiac S100A1 Protein Levels Determine Contractile Performance and Propensity Toward Heart Failure After Myocardial Infarction , 2006, Circulation.

[9]  H. Kitano,et al.  A comprehensive map of the toll-like receptor signaling network , 2006, Molecular systems biology.

[10]  R. Huber,et al.  Handbook of metalloproteins , 2006 .

[11]  Y. Zou,et al.  Receptor for Advanced-Glycation End Products: Key Modulator of Myocardial Ischemic Injury , 2006, Circulation.

[12]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[13]  H. Katus,et al.  Therapeutic Use of Ultrasound Targeted Microbubble Destruction: A Review of Non-Cardiac Applications , 2006, Ultraschall in der Medizin.

[14]  D. Mayer,et al.  S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells. , 2006, Experimental cell research.

[15]  M. Völkers,et al.  S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  Godfrey L. Smith,et al.  S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. , 2005, Journal of molecular and cellular cardiology.

[17]  V. Mehra,et al.  Cytokines and cardiovascular disease , 2005, Journal of leukocyte biology.

[18]  R. Ramasamy,et al.  Aldose Reductase and AGE‐RAGE Pathways: Key Players in Myocardial Ischemic Injury , 2005, Annals of the New York Academy of Sciences.

[19]  M. Boerries,et al.  Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes , 2005, Journal of Cell Science.

[20]  M. Boerries,et al.  Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. , 2004, The Journal of clinical investigation.

[21]  E. Pålsson-McDermott,et al.  Signal transduction by the lipopolysaccharide receptor, Toll‐like receptor‐4 , 2004, Immunology.

[22]  C. Heizmann,et al.  S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). , 2004, Biochemical and biophysical research communications.

[23]  K. Walley,et al.  Novel regulatory mechanism of cardiomyocyte contractility involving ICAM-1 and the cytoskeleton. , 2004, American journal of physiology. Heart and circulatory physiology.

[24]  J. Wautier,et al.  Protein Glycation: A Firm Link to Endothelial Cell Dysfunction , 2004, Circulation research.

[25]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[26]  Brown Ma,et al.  NF-kappaB action in sepsis: the innate immune system and the heart. , 2004 .

[27]  Raffi Bekeredjian,et al.  Effects of ultrasound-targeted microbubble destruction on cardiac gene expression. , 2004, Ultrasound in medicine & biology.

[28]  A. Remppis,et al.  S100A1 gene transfer: a strategy to strengthen engineered cardiac grafts , 2004, The journal of gene medicine.

[29]  W. Claycomb,et al.  Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. , 2004, American journal of physiology. Heart and circulatory physiology.

[30]  D. Figarella-Branger,et al.  Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies , 2003, Muscle & nerve.

[31]  M. Boerries,et al.  Extracellular S100A1 Protein Inhibits Apoptosis in Ventricular Cardiomyocytes via Activation of the Extracellular Signal-regulated Protein Kinase 1/2 (ERK1/2)* , 2003, Journal of Biological Chemistry.

[32]  A. Remppis,et al.  Transgenic Overexpression of the Ca2+-binding Protein S100A1 in the Heart Leads to Increased in Vivo Myocardial Contractile Performance* , 2003, Journal of Biological Chemistry.

[33]  Raffi Bekeredjian,et al.  Ultrasound-Targeted Microbubble Destruction Can Repeatedly Direct Highly Specific Plasmid Expression to the Heart , 2003, Circulation.

[34]  S. Akira,et al.  Role of adapters in Toll-like receptor signalling. , 2003, Biochemical Society transactions.

[35]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[36]  P. Rouleau,et al.  Proinflammatory Activities of S100: Proteins S100A8, S100A9, and S100A8/A9 Induce Neutrophil Chemotaxis and Adhesion 1 , 2003, The Journal of Immunology.

[37]  D. Mann,et al.  CD14-Deficient Mice Are Protected Against Lipopolysaccharide-Induced Cardiac Inflammation and Left Ventricular Dysfunction , 2002, Circulation.

[38]  C. Visser,et al.  Intercellular Adhesion Molecule‐1 in the Heart , 2002, Annals of the New York Academy of Sciences.

[39]  S. Takasawa,et al.  Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. , 2002, Journal of molecular and cellular cardiology.

[40]  Godfrey L. Smith,et al.  S100A1: A regulator of myocardial contractility , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  H. Huttunen,et al.  Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation* , 2000, The Journal of Biological Chemistry.

[42]  K. Walley,et al.  Endotoxin infusion in rats induces apoptotic and survival pathways in hearts. , 2000, American journal of physiology. Heart and circulatory physiology.

[43]  R. de Waal Malefyt,et al.  Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. , 2000, International immunology.

[44]  S. Dower,et al.  Identification of Two Major Sites in the Type I Interleukin-1 Receptor Cytoplasmic Region Responsible for Coupling to Pro-inflammatory Signaling Pathways* , 2000, The Journal of Biological Chemistry.

[45]  M. G. Simms,et al.  Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion. , 1999, American journal of physiology. Heart and circulatory physiology.

[46]  M. Neurath,et al.  RAGE Mediates a Novel Proinflammatory Axis A Central Cell Surface Receptor for S100/Calgranulin Polypeptides , 1999, Cell.

[47]  J. Hogg,et al.  Leukocyte activation does not mediate myocardial leukocyte retention during endotoxemia in rabbits. , 1998, American journal of physiology. Heart and circulatory physiology.

[48]  N J Izzo,et al.  HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  N. Hogg,et al.  The human S100 protein MRP-14 is a novel activator of the beta 2 integrin Mac-1 on neutrophils. , 1998, Journal of immunology.

[50]  J. Granton,et al.  Leukocytes and decreased left-ventricular contractility during endotoxemia in rabbits. , 1997, American journal of respiratory and critical care medicine.

[51]  Y. Hattori,et al.  Induction of mRNAs for ICAM‐1, VCAM‐1, and ELAM‐1 in cultured rat cardiac myocytes and myocardium in vivo , 1997, Biochemistry and molecular biology international.

[52]  H. Werner,et al.  Nitric oxide synthase inhibition partially prevents decreased LV contractility during endotoxemia. , 1996, The American journal of physiology.

[53]  W. Studer,et al.  Decreased left ventricular contractility during porcine endotoxemia is not prevented by ibuprofen. , 1996, Critical care medicine.

[54]  J. Hogg,et al.  Myocardial morphometric changes related to decreased contractility after endotoxin. , 1996, The American journal of physiology.

[55]  T. Standiford,et al.  Cardiac myocytes release leukocyte-stimulating factors. , 1995, The American journal of physiology.

[56]  H. Werner,et al.  Anti-tumor necrosis factor-alpha prevents decreased ventricular contractility in endotoxemic pigs. , 1995, American journal of respiratory and critical care medicine.

[57]  H. Werner,et al.  Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. , 1995, Journal of applied physiology.

[58]  K. Walley,et al.  Decrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs. , 1994, Journal of applied physiology.

[59]  K. O. Elliston,et al.  Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. , 1992, The Journal of biological chemistry.

[60]  Simon C Watkins,et al.  Negative inotropic effects of cytokines on the heart mediated by nitric oxide. , 1992, Science.

[61]  Cardiovascular Diabetology BioMed Central Original investigation , 2007 .

[62]  W. Jones,et al.  NF-kappaB action in sepsis: the innate immune system and the heart. , 2004, Frontiers in bioscience : a journal and virtual library.

[63]  K. Walley Mechanics and energetics of tumor necrosis factor-alpha in the left ventricle. , 1999, Critical care medicine.

[64]  A. M. Lefer,et al.  Mechanisms of cardiodepression in endotoxin shock. , 1979, Circulatory shock. Supplement.

[65]  Lefer Am Mechanisms of cardiodepression in endotoxin shock. , 1979 .