Regulated expression of a foreign gene targeted to the ischaemic myocardium

Howard Prentice, Nanette Bishopric, Martin N. Hicks, Daryl J. Discher, Xiaosu Wu, Andrew A. Wylie, Keith A Webster

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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 α-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.

Original languageEnglish
Pages (from-to)567-574
Number of pages8
JournalCardiovascular Research
Volume35
Issue number3
DOIs
StatePublished - Sep 1 1997

Fingerprint

Myocardium
Ischemia
Genes
Gene Components
Muscles
Myosin Heavy Chains
Response Elements
Reporter Genes
Genetic Therapy
Myocardial Ischemia
Coronary Artery Disease
Cultured Cells
Plasmids
Hypoxia
Rabbits
Gene Expression
Injections
DNA
Therapeutics

Keywords

  • Cardioprotection
  • Gene therapy
  • Hypoxia
  • Redox

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Prentice, H., Bishopric, N., Hicks, M. N., Discher, D. J., Wu, X., Wylie, A. A., & Webster, K. A. (1997). Regulated expression of a foreign gene targeted to the ischaemic myocardium. Cardiovascular Research, 35(3), 567-574. https://doi.org/10.1016/S0008-6363(97)00158-2

Regulated expression of a foreign gene targeted to the ischaemic myocardium. / Prentice, Howard; Bishopric, Nanette; Hicks, Martin N.; Discher, Daryl J.; Wu, Xiaosu; Wylie, Andrew A.; Webster, Keith A.

In: Cardiovascular Research, Vol. 35, No. 3, 01.09.1997, p. 567-574.

Research output: Contribution to journalArticle

Prentice, H, Bishopric, N, Hicks, MN, Discher, DJ, Wu, X, Wylie, AA & Webster, KA 1997, 'Regulated expression of a foreign gene targeted to the ischaemic myocardium', Cardiovascular Research, vol. 35, no. 3, pp. 567-574. https://doi.org/10.1016/S0008-6363(97)00158-2
Prentice H, Bishopric N, Hicks MN, Discher DJ, Wu X, Wylie AA et al. Regulated expression of a foreign gene targeted to the ischaemic myocardium. Cardiovascular Research. 1997 Sep 1;35(3):567-574. https://doi.org/10.1016/S0008-6363(97)00158-2
Prentice, Howard ; Bishopric, Nanette ; Hicks, Martin N. ; Discher, Daryl J. ; Wu, Xiaosu ; Wylie, Andrew A. ; Webster, Keith A. / Regulated expression of a foreign gene targeted to the ischaemic myocardium. In: Cardiovascular Research. 1997 ; Vol. 35, No. 3. pp. 567-574.
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