RESEARCH ARTICLE
Cardiac functional improvement by a human Bcl-2
transgene in a mouse model of ischemia/
reperfusion injury
Vale
Â
rie Brocheriou
1
Albert A. Hage
Á
ge
2
Abdou Oubenaõ
È
ssa
3
Martine Lambert
1
Vincent O. Mallet
1
Micheline Duriez
4
Michel Wassef
5
Axel Kahn
1
Philippe Menasche
Â
6
He
Â
le
Á
ne Gilgenkrantz
1
*
1
U.129 INSERM, ICGM, 24 Rue du
Faubourg St Jacques, 75014 Paris,
France
2
Faculte
Â
de Me
Â
decine Necker-Enfants
Malades, Universite
Â
Rene
Â
Descartes-
Paris V, 156 rue de Vaugirard,
75730 Paris Cedex 15, France
3
U.127 INSERM, Ho
Ã
pital
Lariboisie
Á
re, 41 Bd de la Chapelle,
75475 Paris, France
4
U.141 INSERM, IFR Circulation
Paris 7, Ho
Ã
pital Lariboisie
Á
re, 41 Bd
de la Chapelle, 75475 Paris, France
5
Anatomopathology Department,
Ho
Ã
pital Lariboisie
Á
re, 41 Bd de la
Chapelle, 75475 Paris, France
6
Department of Cardiovascular
Surgery, Ho
Ã
pital Bichat, 46 rue
Henri Huchard, 75018 Paris, France
*Correspondence to: He
Â
le
Á
ne
Gilgenkrantz, U.129 INSERM, ICGM,
24 Rue du Faubourg St Jacques,
75014 Paris, France.
E-mail: gilgenkrantz@
icgm.cochin.inserm.fr
Received: 15 May 2000
Revised: 28 June 2000
Accepted: 3 July 2000
Published online: 4 July 2000
Abstract
Background Apoptosis has been shown to contribute to myocardial
reperfusion injury. It has been suggested that, in reducing the apoptotic
component within the ischemic area at risk, Bcl-2 overexpression could lead
to a ventricular function improvement.
Methods Transgenic mice overexpressing the anti-apoptotic human Bcl-2
cDNA in heart were subjected to a 1-h left coronary artery occlusion followed
by a 24-h reperfusion. At the end of the experiment, left ventricular function
was assessed by two-dimensional echocardiography. After sacri®ce, the area
at risk (AR) and the infarct area (IA) were determined by Evans blue and
triphenyltetrazolium chloride staining, respectively. The extent of apoptosis
was assessed by the TUNEL method. Non-transgenic littermates served as
controls.
Results Baseline AR was not different between Bcl-2 transgenic mice and
their wild-type littermates. In contrast, left ventricular ejection fraction was
signi®cantly improved in the transgenic mice line (61.25t4.0%) compared
to non-transgenic littermates (43.2t5.0%, p<0.01). This functional
amelioration was correlated with a signi®cant reduction of infarct size in
transgenic animals (IA/AR 18.51t3.4% vs 50.83t8.4% in non-transgenic
littermates). Finally, apoptotic nuclei were less numerous in transgenic mice
than in controls as quanti®ed by TUNEL analysis (8.1t2.2% vs 20.6t4.4%).
Conclusions Bcl-2 overexpression is effective in reducing myocardial
reperfusion injury and improving heart function. This bene®t correlates
with a reduction of cardiomyocyte apoptosis. The apoptotic component of
ischemia/reperfusion injury could therefore constitute a new therapeutic
target in the acute phase of myocardial infarction. Copyright # 2000 John
Wiley & Sons, Ltd.
Keywords apoptosis; echocardiography; bcl-2; myocardial infarction;
reperfusion
Introduction
Apoptosis of cardiac myocytes has been documented by numerous studies
during ischemic cardiomyopathy and myocardial infarction [1±7]. In humans,
the area bordering the myocardial infarct has been shown to be even more
prone to these apoptotic events than the infarcted area itself [5±7].
Reperfusion of ischemic myocardium, although reducing morbidity and
mortality, is paradoxically also responsible for an increase in cell mortality,
THE JOURNAL OF GENE MEDICINE
J Gene Med 2000; 2: 326±333.
Copyright # 2000 John Wiley & Sons, Ltd.