Human Coxsackie-Adenovirus Receptor Is Colocalized With Integrins αvβ3 and αvβ5 on the Cardiomyocyte Sarcolemma and Upregulated in Dilated Cardiomyopathy Implications for Cardiotropic Viral Infections

Background The coxsackievirus and adenovirus receptor (CAR) was identified as a common cellular receptor for both viruses, but its biological and pathogenic relevance is uncertain. Knowledge of CAR localization in the human cardiovascular system is limited but important with respect to CAR-dependent viral infections and gene transfer using CAR-dependent viral vectors. Methods and Results Explanted failing hearts from 13 patients (8 with dilated cardiomyopathy [DCM] and 5 with other heart diseases [non-DCM]) and normal donor hearts (n=7) were investigated for the expression levels and subcellular localization of CAR and the adenovirus coreceptors αvβ3 and αvβ5 integrins. CAR immunoreactivity was very low in normal and non-DCM hearts, whereas strong CAR signals occurred at the intercalated discs and sarcolemma in 5 of the 8 DCM hearts (62.5%); these strong signals colocalized with both integrins. In all hearts, CAR was detectable in subendothelial layers of the vessel wall, but not on the luminal endothelia...

[1]  N. Dhalla,et al.  The Hypertrophied Heart , 2012, Progress in Experimental Cardiology.

[2]  H. Fechner,et al.  Trans-complementation of vector replication versus Coxsackie-adenovirus-receptor overexpression to improve transgene expression in poorly permissive cancer cells , 2000, Gene Therapy.

[3]  R. Lefkowitz,et al.  Preservation of myocardial β-adrenergic receptor signaling delays the development of heart failure after myocardial infarction , 2000 .

[4]  H. Fechner,et al.  Adenovirus-based phospholamban antisense expression as a novel approach to improve cardiac contractile dysfunction: comparison of a constitutive viral versus an endothelin-1-responsive cardiac promoter. , 2000, Circulation.

[5]  W. Schaper,et al.  Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. , 2000, Circulation research.

[6]  R. Kuwano,et al.  The coxsackievirus-adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain. , 2000, Brain research. Molecular brain research.

[7]  R. Lefkowitz,et al.  Functional consequences of altering myocardial adrenergic receptor signaling. , 2000, Annual review of physiology.

[8]  R. Kuwano,et al.  Expression of coxsackievirus and adenovirus receptor in hearts of rats with experimental autoimmune myocarditis. , 2000, Circulation research.

[9]  K. Bezstarosti,et al.  SERCA2 and ANF Promoter-Activity Studies in Hypertrophic Cardiomyocytes Using Liposome-, Gene Gun-, and Adenovirus-Mediated Gene Transfer , 2000 .

[10]  E. Kranias,et al.  Genetically engineered models with alterations in cardiac membrane calcium-handling proteins. , 2000, Annual review of physiology.

[11]  R. Lefkowitz,et al.  Preservation of myocardial b-adrenergic receptor signaling delays the development of heart failure after myocardial infarction , 2000 .

[12]  I. Kovesdi,et al.  Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae. , 1999, Science.

[13]  M. Bewley,et al.  Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR. , 1999, Science.

[14]  M. Martone,et al.  Chronic Phospholamban–Sarcoplasmic Reticulum Calcium ATPase Interaction Is the Critical Calcium Cycling Defect in Dilated Cardiomyopathy , 1999, Cell.

[15]  K. Chien,et al.  Signaling pathways for cardiac hypertrophy and failure. , 1999, The New England journal of medicine.

[16]  A. Houtsmuller,et al.  Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers , 1999, Gene Therapy.

[17]  R. Lefkowitz,et al.  Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function , 1999, Gene Therapy.

[18]  R. Lefkowitz,et al.  Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery. , 1999, The Journal of clinical investigation.

[19]  J. Towbin,et al.  Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. , 1999, Circulation.

[20]  J. Towbin,et al.  Etiologies of cardiomyopathy and heart failure , 1999, Nature Medicine.

[21]  R. Kandolf,et al.  Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. , 1999, Circulation.

[22]  D. Brough,et al.  The Coxsackievirus-Adenovirus Receptor Protein Can Function as a Cellular Attachment Protein for Adenovirus Serotypes from Subgroups A, C, D, E, and F , 1998, Journal of Virology.

[23]  U. Walter,et al.  Endogenous or overexpressed cGMP-dependent protein kinases inhibit cAMP-dependent renin release from rat isolated perfused kidney, microdissected glomeruli, and isolated juxtaglomerular cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Randell,et al.  Limited Entry of Adenovirus Vectors into Well-Differentiated Airway Epithelium Is Responsible for Inefficient Gene Transfer , 1998, Journal of Virology.

[25]  J. Bergelson,et al.  The Murine CAR Homolog Is a Receptor for Coxsackie B Viruses and Adenoviruses , 1998, Journal of Virology.

[26]  L. Philipson,et al.  HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Bergelson,et al.  Isolation of a Common Receptor for Coxsackie B Viruses and Adenoviruses 2 and 5 , 1997, Science.

[28]  R. Crystal,et al.  Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis , 1994, Nature Genetics.

[29]  G. Nemerow,et al.  Integrins α v β 3 and α v β 5 promote adenovirus internalization but not virus attachment , 1993, Cell.

[30]  M. Perricaudet,et al.  In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium , 1992, Cell.

[31]  R. Belshe.  Textbook of human virology , 1984 .

[32]  G R HERRMANN,et al.  Congestive heart failure. , 1962, Geriatrics.