title: Induction of coxsackievirus-adenovirus-receptor expression during myocardial tissue formation and remodeling: identification of a cell-to-cell contact-dependent regulatory mechanism.
abstract: BACKGROUND
  The coxsackievirus-adenovirus receptor (CAR) was cloned as a receptor for both viruses, but its primary biological functions and regulatory mechanisms are unknown. CAR was low in healthy adult myocardium, whereas strong CAR reexpression was observed in human dilated cardiomyopathy. The molecular mechanisms of CAR induction in cardiomyocytes are unknown.
  
  
  RESULTS
  We report on CAR regulation during development, CAR induction after myocardial infarction, and cell-to-cell contact-dependent CAR regulation in the rat. The high CAR expression during development in various organs decreased up to 190-fold after birth. After infarction resulting in severe cardiac dysfunction (dP/dt(max), -53%; dP/dt(min), -58%; left ventricular pressure, -45%), CAR was induced locally in cardiomyocytes of the infarct zone, where it was also expressed by capillary-like CD31+ structures and CD18+ interstitial cells, whereas it remained confined to subendothelial layers of arterioles and venules. In cultured cardiomyocytes, endothelin-1, cardiotrophin-1, leukemia-inhibiting factor, and cyclic stretch had no effect on CAR, whereas at high versus low cell density, CAR was suppressed up to 10-fold (P=0.006). Conditioned media from low- or high-density cardiomyocytes or cardiofibroblasts had no effect.
  
  
  CONCLUSIONS
  The locally confined CAR upregulation after infarction makes induction by various humoral factors unlikely, because cardiac dysfunction results in high activities of sympathetic and renin-angiotensin systems and cytokines. The cell culture experiments identify a cell-to-cell contact-dependent mechanism of CAR regulation. Further characterization of the signals linking cell-to-cell interactions to CAR gene expression may provide insight into mechanisms and functional consequences of the generalized CAR induction in dilated cardiomyopathy, and of its local induction after myocardial infarction.
authors.affiliation: Department of Cardiology and Pneumology, Institute of Clinical Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Fechner
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschoepe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hinze
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Felicitas
authors.initials: F
authors.lastname: Escher
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
authors.forename: Dick
authors.initials: D
authors.lastname: Dekkers
authors.forename: Roland
authors.initials: R
authors.lastname: Vetter
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: Jos
authors.initials: J
authors.lastname: Lamers
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018821:CD18 Antigens / Q000096:biosynthesis; D002450:Cell Communication; D002452:Cell Count; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D006439:Hemodynamics; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; C568771:CLMP protein, human; C568773:Clmp protein, rat; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020033:Protein Isoforms; D012333:RNA, Messenger; D011991:Receptors, Virus