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(Circulation. 2001;104:I-303.)
© 2001 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Heat Shock Protein 70 Gene Transfection Protects Mitochondrial and Ventricular Function Against Ischemia-Reperfusion Injury

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

From the Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine, Royal Brompton and Harefield Hospital, Harefield, Middlesex, UK.

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

Background— Upregulation of heat shock protein 70 (HSP70) is beneficial in cardioprotection against ischemia-reperfusion injury, but the mechanism of action is unclear. We studied the role of HSP70 overexpression through gene therapy on mitochondrial function and ventricular recovery in a protocol that mimics clinical donor heart preservation.

Methods and Results— Hemagglutinating virus of Japan (HVJ)-liposome technique was used to transfect isolated rat hearts via intracoronary infusion of either the HSP70 gene (HSP group, n=16) or no gene (CON group, n=16), which was heterotopically transplanted into recipient rats. Four days after surgery, hearts were either perfused on a Langendorff apparatus for 30 minutes at 37°C (preischemia studies [n=8/group]) or perfused for 30 minutes at 37°C, cardioplegically arrested for 4 hours at 4°C, and reperfused for 30 minutes at 37°C (postischemia studies [n=8/group]). Western blotting and immunohistochemistry confirmed HSP70 upregulation in the HSP group. Postischemic mitochondrial respiratory control indices (RCIs) were significantly better preserved in HSP than in CON hearts: NAD⁺-linked RCI values were 9.54±1.1 versus 10.62±0.46 before ischemia (NS) but 7.98±0.69 versus 1.28±0.15 after ischemia (P<0.05), and FAD-linked RCI values were 6.87±0.88 versus 6.73±0.93 before ischemia (NS) but 4.26±0.41 versus 1.34±0.13 after ischemia (P<0.05). Postischemic recovery of mechanical function was greater in HSP than in CON hearts: left ventricular developed pressure recovery was 72.4±6.4% versus 59.7±5.3% (P<0.05), maximum dP/dt recovery was 77.9±6.6% versus 52.3±5.2% (P<0.05), and minimum dP/dt recovery was 72.4±7.2% versus 54.8±6.9% (P<0.05). Creatine kinase release in coronary effluent after reperfusion was 0.20±0.04 versus 0.34±0.06 IU · min^-1 · g wet wt^-1 (P<0.05) in HSP versus in CON hearts.

Conclusions— HSP70 upregulation protects mitochondrial function after ischemia-reperfusion injury; this was associated with improved preservation of ventricular function. Protection of mitochondrial function may be important in the development of future cardioprotective strategies.

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