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(Circulation. 2003;107:1170.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Decreased Efficiency of Adenovirus-Mediated Gene Transfer in Aging Cardiomyocytes

Catherine Communal, PhD; Fawzia Huq, MD; Djamel Lebeche, PhD; Celine Mestel; Judith K. Gwathmey, VMD, PhD; Roger J. Hajjar, MD

From the Cardiovascular Research Center (F.H., D.L., C.M., R.J.H.), Massachusetts General Hospital and Harvard Medical School (J.K.G.), Boston, Mass, and INSERM U572 (C.C.), Hôpital Lariboisière, Paris, France.

Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Charlestown, MA 02129. E-mail hajjar{at}cvrc.mgh.harvard.edu

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.

Methods and Results— When infected with adenovirus containing ß-galactosidase (ß-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, ₃ß₁ was downregulated in aging cardiac myocytes. Blocking the ß₁ component of ₃ß₁ further decreased infectivity, suggesting that the interaction between the penton base of the adenovirus and ß₁ 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.

Key Words: aging • gene therapy • myocytes • viruses • receptors

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