Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts

Ingo Kutschka; Theo Kofidis; Ian Y. Chen; Georges Von Degenfeld; Monika Zwierzchoniewska; Grant Hoyt; Takayasu Arai; Darren R. Lebl; Stephen L. Hendry; Ahmad Y. Sheikh; David T. Cooke; Andrew Connolly; Helen M. Blau; Sanjiv S. Gambhir; Robert C. Robbins

doi:10.1161/CIRCULATIONAHA.105.001370

Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts

Ingo Kutschka, Theo Kofidis, Ian Y. Chen, Georges Von Degenfeld, Monika Zwierzchoniewska, Grant Hoyt, Takayasu Arai, Darren R. Lebl, Stephen L. Hendry, Ahmad Y. Sheikh, David T. Cooke, Andrew Connolly, Helen M. Blau, Sanjiv S. Gambhir, Robert C. Robbins

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

BACKGROUND - Cell transplantation for myocardial repair is limited by early cell death. Gene therapy with human Bcl-2 (hBcl-2) has been shown to attenuate apoptosis in the experimental setting. Therefore, we studied the potential benefit of hBcl-2 transgene expression on the survival of cardiomyoblast grafts in ischemic rat hearts. METHODS AND RESULTS - H9c2 rat cardiomyoblasts were genetically modified to express both firefly luciferase and green fluorescent protein (mH9c2). The cells were then transduced with adenovirus carrying hBcl-2 (AdCMVhBcl-2/mH9c2). Lewis rats underwent ligation of the left anterior descending artery (LAD) to induce a sizable left ventricular (LV) infarct. Hearts were explanted and the infarcted region was restored using collagen matrix (CM) seeded with 1×10 mH9c2 cells (n=9) or AdCMVhBcl-2/mH9c2 cells (n=9). Control animals received CM alone (n=6) or no infarct (n=6). Restored hearts were transplanted into the abdomen of syngeneic recipients in a "working heart" model. Cell survival was evaluated using optical bioluminescence imaging on days 1, 5, 8, 14, and 28 after surgery. The left heart function was assessed 4 weeks postoperatively using echocardiography and magnetic resonance imaging. During 4 weeks after surgery, the optical imaging signal for the AdCMVhBCL2/mH9c2 group was significantly (P<0.05) higher than that of the mH9c2-control group. Both grafts led to better fractional shortening (AdCMVhBcl-2/mH9c2: 0.21±0.03; mH9c2: 0.21±0.04; control: 0.15±0.03; P=0.04) and ejection fraction (AdCMVhBcl-2/mH9c2: 47.0±6.2; mH9c2: 48.7±6.1; control: 34.3±6.0; P=0.02) compared with controls. Importantly, no malignant cells were found in postmortem histology. CONCLUSION - Transduction of mH9c2 cardiomyoblasts with AdCMVhBcl-2 increased graft survival in ischemic rat myocardium without causing malignancies. Both AdCMVhBcl-2/mH9c2 and mH9c2 grafts improved LV function.

Original language	English (US)
Pages (from-to)	I174-I180
Journal	Circulation
Volume	114
Issue number	SUPPL. 1
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.105.001370
State	Published - Jul 2006
Externally published	Yes

Keywords

Apoptosis
Cells
Gene therapy
Grafting
Myocardial infarction

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.105.001370

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Kutschka, I., Kofidis, T., Chen, I. Y., Von Degenfeld, G., Zwierzchoniewska, M., Hoyt, G., Arai, T., Lebl, D. R., Hendry, S. L., Sheikh, A. Y., Cooke, D. T., Connolly, A., Blau, H. M., Gambhir, S. S., & Robbins, R. C. (2006). Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts. Circulation, 114(SUPPL. 1), I174-I180. https://doi.org/10.1161/CIRCULATIONAHA.105.001370

Kutschka, I, Kofidis, T, Chen, IY, Von Degenfeld, G, Zwierzchoniewska, M, Hoyt, G, Arai, T, Lebl, DR, Hendry, SL, Sheikh, AY, Cooke, DT, Connolly, A, Blau, HM, Gambhir, SS & Robbins, RC 2006, 'Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts', Circulation, vol. 114, no. SUPPL. 1, pp. I174-I180. https://doi.org/10.1161/CIRCULATIONAHA.105.001370

@article{884376b4370b4275ae93c3daeae5e25c,

title = "Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts",

abstract = "BACKGROUND - Cell transplantation for myocardial repair is limited by early cell death. Gene therapy with human Bcl-2 (hBcl-2) has been shown to attenuate apoptosis in the experimental setting. Therefore, we studied the potential benefit of hBcl-2 transgene expression on the survival of cardiomyoblast grafts in ischemic rat hearts. METHODS AND RESULTS - H9c2 rat cardiomyoblasts were genetically modified to express both firefly luciferase and green fluorescent protein (mH9c2). The cells were then transduced with adenovirus carrying hBcl-2 (AdCMVhBcl-2/mH9c2). Lewis rats underwent ligation of the left anterior descending artery (LAD) to induce a sizable left ventricular (LV) infarct. Hearts were explanted and the infarcted region was restored using collagen matrix (CM) seeded with 1×10 mH9c2 cells (n=9) or AdCMVhBcl-2/mH9c2 cells (n=9). Control animals received CM alone (n=6) or no infarct (n=6). Restored hearts were transplanted into the abdomen of syngeneic recipients in a {"}working heart{"} model. Cell survival was evaluated using optical bioluminescence imaging on days 1, 5, 8, 14, and 28 after surgery. The left heart function was assessed 4 weeks postoperatively using echocardiography and magnetic resonance imaging. During 4 weeks after surgery, the optical imaging signal for the AdCMVhBCL2/mH9c2 group was significantly (P<0.05) higher than that of the mH9c2-control group. Both grafts led to better fractional shortening (AdCMVhBcl-2/mH9c2: 0.21±0.03; mH9c2: 0.21±0.04; control: 0.15±0.03; P=0.04) and ejection fraction (AdCMVhBcl-2/mH9c2: 47.0±6.2; mH9c2: 48.7±6.1; control: 34.3±6.0; P=0.02) compared with controls. Importantly, no malignant cells were found in postmortem histology. CONCLUSION - Transduction of mH9c2 cardiomyoblasts with AdCMVhBcl-2 increased graft survival in ischemic rat myocardium without causing malignancies. Both AdCMVhBcl-2/mH9c2 and mH9c2 grafts improved LV function.",

keywords = "Apoptosis, Cells, Gene therapy, Grafting, Myocardial infarction",

author = "Ingo Kutschka and Theo Kofidis and Chen, {Ian Y.} and {Von Degenfeld}, Georges and Monika Zwierzchoniewska and Grant Hoyt and Takayasu Arai and Lebl, {Darren R.} and Hendry, {Stephen L.} and Sheikh, {Ahmad Y.} and Cooke, {David T.} and Andrew Connolly and Blau, {Helen M.} and Gambhir, {Sanjiv S.} and Robbins, {Robert C.}",

year = "2006",

month = jul,

doi = "10.1161/CIRCULATIONAHA.105.001370",

language = "English (US)",

volume = "114",

pages = "I174--I180",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "SUPPL. 1",

}

TY - JOUR

T1 - Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts

AU - Kutschka, Ingo

AU - Kofidis, Theo

AU - Chen, Ian Y.

AU - Von Degenfeld, Georges

AU - Zwierzchoniewska, Monika

AU - Hoyt, Grant

AU - Arai, Takayasu

AU - Lebl, Darren R.

AU - Hendry, Stephen L.

AU - Sheikh, Ahmad Y.

AU - Cooke, David T.

AU - Connolly, Andrew

AU - Blau, Helen M.

AU - Gambhir, Sanjiv S.

AU - Robbins, Robert C.

PY - 2006/7

Y1 - 2006/7

N2 - BACKGROUND - Cell transplantation for myocardial repair is limited by early cell death. Gene therapy with human Bcl-2 (hBcl-2) has been shown to attenuate apoptosis in the experimental setting. Therefore, we studied the potential benefit of hBcl-2 transgene expression on the survival of cardiomyoblast grafts in ischemic rat hearts. METHODS AND RESULTS - H9c2 rat cardiomyoblasts were genetically modified to express both firefly luciferase and green fluorescent protein (mH9c2). The cells were then transduced with adenovirus carrying hBcl-2 (AdCMVhBcl-2/mH9c2). Lewis rats underwent ligation of the left anterior descending artery (LAD) to induce a sizable left ventricular (LV) infarct. Hearts were explanted and the infarcted region was restored using collagen matrix (CM) seeded with 1×10 mH9c2 cells (n=9) or AdCMVhBcl-2/mH9c2 cells (n=9). Control animals received CM alone (n=6) or no infarct (n=6). Restored hearts were transplanted into the abdomen of syngeneic recipients in a "working heart" model. Cell survival was evaluated using optical bioluminescence imaging on days 1, 5, 8, 14, and 28 after surgery. The left heart function was assessed 4 weeks postoperatively using echocardiography and magnetic resonance imaging. During 4 weeks after surgery, the optical imaging signal for the AdCMVhBCL2/mH9c2 group was significantly (P<0.05) higher than that of the mH9c2-control group. Both grafts led to better fractional shortening (AdCMVhBcl-2/mH9c2: 0.21±0.03; mH9c2: 0.21±0.04; control: 0.15±0.03; P=0.04) and ejection fraction (AdCMVhBcl-2/mH9c2: 47.0±6.2; mH9c2: 48.7±6.1; control: 34.3±6.0; P=0.02) compared with controls. Importantly, no malignant cells were found in postmortem histology. CONCLUSION - Transduction of mH9c2 cardiomyoblasts with AdCMVhBcl-2 increased graft survival in ischemic rat myocardium without causing malignancies. Both AdCMVhBcl-2/mH9c2 and mH9c2 grafts improved LV function.

AB - BACKGROUND - Cell transplantation for myocardial repair is limited by early cell death. Gene therapy with human Bcl-2 (hBcl-2) has been shown to attenuate apoptosis in the experimental setting. Therefore, we studied the potential benefit of hBcl-2 transgene expression on the survival of cardiomyoblast grafts in ischemic rat hearts. METHODS AND RESULTS - H9c2 rat cardiomyoblasts were genetically modified to express both firefly luciferase and green fluorescent protein (mH9c2). The cells were then transduced with adenovirus carrying hBcl-2 (AdCMVhBcl-2/mH9c2). Lewis rats underwent ligation of the left anterior descending artery (LAD) to induce a sizable left ventricular (LV) infarct. Hearts were explanted and the infarcted region was restored using collagen matrix (CM) seeded with 1×10 mH9c2 cells (n=9) or AdCMVhBcl-2/mH9c2 cells (n=9). Control animals received CM alone (n=6) or no infarct (n=6). Restored hearts were transplanted into the abdomen of syngeneic recipients in a "working heart" model. Cell survival was evaluated using optical bioluminescence imaging on days 1, 5, 8, 14, and 28 after surgery. The left heart function was assessed 4 weeks postoperatively using echocardiography and magnetic resonance imaging. During 4 weeks after surgery, the optical imaging signal for the AdCMVhBCL2/mH9c2 group was significantly (P<0.05) higher than that of the mH9c2-control group. Both grafts led to better fractional shortening (AdCMVhBcl-2/mH9c2: 0.21±0.03; mH9c2: 0.21±0.04; control: 0.15±0.03; P=0.04) and ejection fraction (AdCMVhBcl-2/mH9c2: 47.0±6.2; mH9c2: 48.7±6.1; control: 34.3±6.0; P=0.02) compared with controls. Importantly, no malignant cells were found in postmortem histology. CONCLUSION - Transduction of mH9c2 cardiomyoblasts with AdCMVhBcl-2 increased graft survival in ischemic rat myocardium without causing malignancies. Both AdCMVhBcl-2/mH9c2 and mH9c2 grafts improved LV function.

KW - Apoptosis

KW - Cells

KW - Gene therapy

KW - Grafting

KW - Myocardial infarction

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UR - http://www.scopus.com/inward/citedby.url?scp=33747190635&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.105.001370

DO - 10.1161/CIRCULATIONAHA.105.001370

M3 - Article

C2 - 16820569

AN - SCOPUS:33747190635

SN - 0009-7322

VL - 114

SP - I174-I180

JO - Circulation

JF - Circulation

IS - SUPPL. 1

ER -

Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts

Abstract

Keywords

ASJC Scopus subject areas

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