title: Decreased efficiency of adenovirus-mediated gene transfer in aging cardiomyocytes.
abstract: BACKGROUND
  Aging is an independent risk factor for the development of cardiovascular disease. Clinical application of myocardial gene transfer may be best suited in the elderly. In vivo gene transfer by adenovirus is less efficient in aging myocardium.
  
  
  RESULTS
  When infected with adenovirus containing beta-galactosidase (beta-gal) and green fluorescent protein (GFP) driven by cytomegalovirus promoters in vitro, aging rat cardiac myocytes exhibit significantly lower infectivity and delayed transgene expression compared with adult controls. Abnormalities of viral internalization may be one mechanism accounting for this difference. To investigate this, we studied expression levels of the coxsackievirus and adenovirus receptor (CAR) as well as other potential integrins involved in the internalization of adenoviruses. CAR expression tended to be upregulated whereas among potential integrins, alpha(3)beta(1) was downregulated in aging cardiac myocytes. Blocking the beta(1) component of alpha(3)beta(1) further decreased infectivity, suggesting that the interaction between the penton base of the adenovirus and beta(1) maybe a crucial component of the viral entry mechanism.
  
  
  CONCLUSIONS
  These results suggest that it is integrin-stimulated internalization rather than the adenovirus-CAR interaction that plays a vital role in adenoviral entry. The downregulation of integrins observed in senescent cells may be a key mechanism accounting for the decrease in viral infectivity seen in these cells. These findings have implications for the gene therapy treatment of myocardial failure in the elderly.
authors.affiliation: INSERM U572, Hôpital Lariboisière, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Communal
authors.forename: Fawzia
authors.initials: F
authors.lastname: Huq
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Celine
authors.initials: C
authors.lastname: Mestel
authors.forename: Judith K
authors.initials: JK
authors.lastname: Gwathmey
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005822:Genetic Vectors; D016023:Integrins / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000821:virology*; D051381:Rats; D011916:Rats, Inbred F344; D011991:Receptors, Virus / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: C568773:Clmp protein, rat; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D011991:Receptors, Virus