Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer.
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 beta-galactosidase gene (DM + Ad.betaGal) 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 EDP(0.1) 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.betaGal/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.
Sakata
Susumu
S
Cardiovascular Research Center, Cardiology Laboratory of Integrative Physiology & Imaging, Massachusetts General Hospital, 149 13th Street, CNY-4, Charlestown, MA 02129, USA.
Lebeche
Djamel
D
Sakata
Yuri
Y
Sakata
Naoya
N
Chemaly
Elie R
ER
Liang
Li Fan
LF
Padmanabhan
Prabhu
P
Konishi
Noboru
N
Takaki
Miyako
M
del Monte
Federica
F
Hajjar
Roger J
RJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D020334:Rats, Inbred OLETF; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D016277:Ventricular Function, Left / Q000235:genetics / Q000502:physiology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D001616:beta-Galactosidase; D000252:Calcium-Transporting ATPases; D002118:Calcium