Protection from Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System

Yao Liang Tang, Yi Tang, Y. Clare Zhang, Keping Qian, Leping Shen, M. Ian Phillips

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-α. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%±4.8% versus 62.5%±3.3%, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-I gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

Original languageEnglish (US)
Pages (from-to)746-751
Number of pages6
JournalHypertension
Volume43
Issue number4
DOIs
StatePublished - Apr 1 2004
Externally publishedYes

Fingerprint

Heart Injuries
Heme Oxygenase-1
Plasmids
Genes
Myocardial Infarction
Switch Genes
Cardiac Catheters
Hypoxia-Inducible Factor 1
Myosin Light Chains
Caspase 3
Genetic Therapy
Myocardium
Fibrosis
Ischemia

Keywords

  • Genes
  • Heart
  • Ischemia

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Protection from Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System. / Tang, Yao Liang; Tang, Yi; Zhang, Y. Clare; Qian, Keping; Shen, Leping; Phillips, M. Ian.

In: Hypertension, Vol. 43, No. 4, 01.04.2004, p. 746-751.

Research output: Contribution to journalArticle

Tang, Yao Liang ; Tang, Yi ; Zhang, Y. Clare ; Qian, Keping ; Shen, Leping ; Phillips, M. Ian. / Protection from Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System. In: Hypertension. 2004 ; Vol. 43, No. 4. pp. 746-751.
@article{a3ff80a4c8ce4c71897db8dfe55c73a3,
title = "Protection from Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System",
abstract = "Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-α. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0{\%}±4.8{\%} versus 62.5{\%}±3.3{\%}, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-I gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.",
keywords = "Genes, Heart, Ischemia",
author = "Tang, {Yao Liang} and Yi Tang and Zhang, {Y. Clare} and Keping Qian and Leping Shen and Phillips, {M. Ian}",
year = "2004",
month = "4",
day = "1",
doi = "10.1161/01.HYP.0000120152.27263.87",
language = "English (US)",
volume = "43",
pages = "746--751",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Protection from Ischemic Heart Injury by a Vigilant Heme Oxygenase-1 Plasmid System

AU - Tang, Yao Liang

AU - Tang, Yi

AU - Zhang, Y. Clare

AU - Qian, Keping

AU - Shen, Leping

AU - Phillips, M. Ian

PY - 2004/4/1

Y1 - 2004/4/1

N2 - Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-α. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%±4.8% versus 62.5%±3.3%, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-I gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

AB - Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-α. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%±4.8% versus 62.5%±3.3%, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-I gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

KW - Genes

KW - Heart

KW - Ischemia

UR - http://www.scopus.com/inward/record.url?scp=1642501642&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642501642&partnerID=8YFLogxK

U2 - 10.1161/01.HYP.0000120152.27263.87

DO - 10.1161/01.HYP.0000120152.27263.87

M3 - Article

VL - 43

SP - 746

EP - 751

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 4

ER -