This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jayakumar, J. Articles by Yacoub, M. H. Search for Related Content PubMed PubMed Citation Articles by Jayakumar, J. Articles by Yacoub, M. H. Pubmed/NCBI databases Medline Plus Health Information Genes and Gene Therapy Heart Transplantation Related Collections Gene therapy CV surgery: transplantation, ventricular assistance, cardiomyopathy

(Circulation. 2000;102:III-302.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Gene Therapy for Myocardial Protection

Transfection of Donor Hearts With Heat Shock Protein 70 Gene Protects Cardiac Function Against Ischemia-Reperfusion Injury

Jay Jayakumar, MD; Ken Suzuki, MD, PhD; Mak Khan, PhD; Ryszard T. Smolenski, MD, PhD; Aldo Farrell, PhD; Najma Latif, PhD; Olivier Raisky, MD; Haitham Abunasra, MD; Ivan A. Sammut, PhD; Bari Murtuza, MD; Mohamed Amrani, MD, PhD; Magdi H. Yacoub, DSc, FRS

From the Department of Cardiothoracic Surgery, National Heart and Lung Institute, Harefield Hospital, Harefield, Middlesex, UK.

Correspondence to Professor Sir Magdi H. Yacoub, DSc, FRS, Department of Cardiothoracic Surgery, National Heart and Lung Institute, Harefield Hospital, Harefield, Middlesex, UB9 6JH, UK. E-mail jay.jayakumar{at}harefield.nthames.nhs.uk

Background—Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endothelial function in a protocol mimicking clinical heart preservation.

Methods and Results—Rat hearts were infused ex vivo with Hemagglutinating Virus of Japan–liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas’ No. 1 cardioplegia for 4 hours at 4°C, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in reperfusion effluent. Hearts underwent Western blotting and immunohistochemistry to confirm HSP70 overexpression. Postischemic recovery of mechanical function (% preischemic±SEM) was greater in HSP versus CON: Left ventricular developed pressure recovery was 76.7±3.9% versus 60.5±3.1% (P<0.05); dP/dtmax recovery was 79.4±4.9% versus 56.2±3.2% (P<0.05); dP/dtmin recovery was 74.8±4.6% versus 57.3±3.6% (P<0.05). Creatine kinase release was attenuated in HSP versus CON: 0.22±0.02 versus 0.32±0.04 IU/min/g wet wt. (P<0.05). Recovery of coronary flow was greater in HSP versus CON: 76.5±3.8% versus 59.2±3.2% (P<0.05). Recovery of coronary response to 5-hydroxytryptamine (5x10^-5 mol/L) was 55.6±4.7% versus 23.9±3.2% (P<0.05); recovery of coronary response to glyceryltrinitrate (15 mg/L) was not different between HSP and CON: 87.4±6.9% versus 84.3±5.8% (NS).

Conclusions—In a clinically relevant donor heart preservation protocol, HSP70 gene transfection protects both mechanical and endothelial function.

Key Words: genes • proteins • ischemia • reperfusion • transplantation

This article has been cited by other articles:

				H. T. Tevaearai, G. B. Walton, A. D. Eckhart, J. R. Keys, and W. J. Koch Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated {beta}-adrenergic signaling modulation Eur. J. Cardiothorac. Surg., November 1, 2002; 22(5): 733 - 737. [Abstract] [Full Text] [PDF]

				K. Christopher, T. F. Mueller, C. Ma, Y. Liang, and D. L. Perkins Analysis of the Innate and Adaptive Phases of Allograft Rejection by Cluster Analysis of Transcriptional Profiles J. Immunol., July 1, 2002; 169(1): 522 - 530. [Abstract] [Full Text] [PDF]

				I. A. Sammut, J. Jayakumar, N. Latif, S. Rothery, N. J. Severs, R. T. Smolenski, T. E. Bates, and M. H. Yacoub Heat Stress Contributes to the Enhancement of Cardiac Mitochondrial Complex Activity Am. J. Pathol., May 1, 2001; 158(5): 1821 - 1831. [Abstract] [Full Text] [PDF]