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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2267.)
© 2006 American Heart Association, Inc.

Vascular Biology

Beta-Adrenoceptor Blockade Markedly Attenuates Transgene Expression From Cytomegalovirus Promoters Within the Cardiovascular System

Husein K. Salem; Parisa Ranjzad; Anita Driessen; Clare E. Appleby; Anthony M. Heagerty; Paul A. Kingston

From the Vascular Gene Therapy Unit (H.K.S., P.R., C.E.A., P.A.K.), University of Manchester, Manchester, UK; Medtronic Bakken Research Centre B.V. (A.D.), Maastricht, Netherlands; Department of Medicine (A.M.H.), University of Manchester, Manchester, UK.

Correspondence to Dr Paul Kingston, Room 3.26, Core Technology Facility, 46 Grafton Street, Manchester, M13 9NT, UK. E-mail paul.a.kingston{at}manchester.ac.uk

Objectives— The major immediate–early cytomegalovirus enhancer/promoter (MIECMV), widely used in cardiovascular gene therapy, contains several positively regulatory cAMP response elements (CRE). Catecholamine signaling via ß-adrenoceptors might increase transgene expression from MIECMV, and if so, ß-blockers may have a detrimental effect on the efficacy of clinical cardiovascular gene therapy strategies.

Methods and Results— Cultured smooth muscle cells were exposed to isoprenaline, atenolol, or propranolol, alone and in combination before infection with adenoviruses expressing ß-galactosidase. ß-galactosidase expression was assayed 72 hours later. Isoprenaline increased transgene expression from MIECMV up to 8-fold (P<0.001), but had no effect on a promoter containing no CRE. The effect of isoprenaline was inhibited by ß-blockade and by specific CRE-decoy oligonucleotides. ß-blockers did not reduce transgene expression below basal levels. After adenovirus-mediated porcine intracoronary gene transfer, however, ß-blockade reduced ß-galactosidase expression by up to 250-fold compared with non-ß-blocked animals (P<0.01).

Conclusions— Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature. ß-blocker-mediated suppression of transgene expression from MIECMV in vascular tissues has a significant bearing on clinical studies of cardiovascular gene transfer. This is the first described interaction to our knowledge between widely prescribed pharmaceuticals and a commonly used promoter of clinical transgene expression.

The major immediate–early cytomegalovirus enhancer/promoter (MIECMV) is used extensively in studies of clinical cardiovascular gene transfer. Transgene expression from MIECMV within the vasculature is suppressed by ß-blockade. This interaction is highly pertinent to the interpretation of current studies and to the planning of future studies of therapeutic cardiovascular gene transfer.

Key Words: ß-adrenergic receptor blockers • catecholamines • gene therapy