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Cardiovascular Research 1997 35(3):567-574; doi:10.1016/S0008-6363(97)00158-2
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Regulated expression of a foreign gene targeted to the ischaemic myocardium

Howard Prenticed, Nanette H Bishoprica,b, Martin N Hicksc, Daryl J Dischera,b, Xiaosu Wua, Andrew A Wylied and Keith A Webstera,b,*

aPharmaceutical Discovery Division, SRI International, Menlo Park, CA, USA
bDepartment of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, USA
cDepartment of Medical Cardiology, Glasgow Royal Infirmary, University of Glasgow, Glasgow, UK
dDivision of Molecular Genetics, Institute of Biomedical and Life Sciences and Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

* Corresponding author. Department of Molecular and Cellular Pharmacology, Rosenstiel Medical Science Building, Rm. 6038, University of Miami, 1600 NW Tenth Avenue, Miami, FL 33136, USA. Tel.: +1 (305) 243-6779; fax: +1 (305) 243-4555; e-mail: kwebster@chroma.med.miami.edu

Objectives: Regulated expression of transferred foreign genes may be an important feature of gene therapy. Because coronary artery disease often involves intermittent myocardial ischaemia followed by periods of normal cardiac function it will probably be necessary to regulate the expression of putative therapeutic/cardioprotective genes directly in response to ischaemia-associated signals. The objectives of the current study were to develop a combination of gene regulatory components that can be used to target a product to the myocardium and limit the expression of the gene to periods of ischaemic activity. Methods: Expression plasmids were constructed containing muscle-specific promoters and hypoxia-responsive enhancer elements linked to a reporter gene. The regulation of these constructs by hypoxia or experimental ischaemia was measured following transient expression in cultured cells or after direct injection of DNA into the rabbit myocardium. Results: A single set of hypoxia response elements placed immediately upstream of the minimal muscle-specific {alpha}-myosin heavy chain promoter conferred potent positive regulation of this promoter by hypoxia in vitro and by ischaemia in vivo. Induction by ischaemia persisted for at least 4 h and returned to the baseline level within 8 h. Conclusions: Hypoxia responsive regulatory elements, in combination with weak tissue-restricted promoters incorporated into an appropriate vector system may allow controlled expression of a therapeutic gene in ischaemic myocardium.

KEYWORDS Gene therapy; Hypoxia; Cardioprotection; Redox


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