Original Articles
Molecular Therapy (2006) 13, 987–996; doi: 10.1016/j.ymthe.2006.01.002
Mechanical and Metabolic Rescue in a Type II Diabetes Model of Cardiomyopathy by Targeted Gene Transfer
Susumu Sakata1,2, Djamel Lebeche1, Yuri Sakata1, Naoya Sakata1, Elie R. Chemaly1, Li Fan Liang1, Prabhu Padmanabhan1, Noboru Konishi3, Miyako Takaki2, Federica del Monte1 and Roger J. Hajjar1
- 1Cardiovascular Research Center, Cardiology Laboratory of Integrative Physiology & Imaging, Massachusetts General Hospital, 149 13th Street, CNY-4, Charlestown, MA 02129, USA
- 2Department of Physiology II, Nara Medical University, Kashihara, Nara 634-8521, Japan
- 3Department of Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
Correspondence: Roger J. Hajjar, E-mail: rhajjar@partners.org
Received 19 December 2005; Revised 18 January 2006; Accepted 26 January 2006.
Abstract
The Otsuka–Long–Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the 
-galactosidase gene (DM + Ad.Gal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP0.1 was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure–volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.Gal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.
Keywords:
gene therapy, heart failure, SERCA2a, energetic function, diabetes mellitus
Abbreviations:
DM, diabetes mellitus; OLETF, Otsuka–Long–Evans Tokushima Fatty; LETO, Long–Evans Tokushima Otsuka; CHF, congestive heart failure; BW, body weight; BG, blood glucose; SR, sarcoplasmic reticulum; LV, left ventricle or ventricular; RV, right ventricle or ventricular; MHC, myosin heavy chain; CK, creatine kinase; RyR, ryanodine receptor; FKBP12.6, FK506-binding protein; NaCaX, Na+–Ca2+ exchanger; E-C, excitation–contraction; SERCA2a, sarcoplasmic reticulum Ca2+ -ATPase pump; Ad.SERCA2a, adenovirus carrying SERCA2a gene; Ad.Gal, adenovirus carrying -galactosidase gene; LVP, left ventricular pressure; ESPVR, end-systolic pressure–volume relation; EDPVR, end-diastolic pressure–volume relation; ESP0.1, end-systolic pressure at 0.1 ml of intraballoon water; EDP0.1, end-diastolic pressure at 0.1 ml of intraballoon water; PVA, systolic pressure–volume area; VO2, myocardial oxygen consumption per beat; eEmax, equivalent maximal elastance; mLVV, midrange LV volume; ESPmLVV, end-systolic pressure observed at mLVV; PVAmLVV, systolic pressure–volume area at mLVV; TL, logistic time constant
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