title: Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer.
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 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.
authors.affiliation: Cardiovascular Research Center, Cardiology Laboratory of Integrative Physiology & Imaging, Massachusetts General Hospital, 149 13th Street, CNY-4, Charlestown, MA 02129, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakata
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sakata
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakata
authors.forename: Elie R
authors.initials: ER
authors.lastname: Chemaly
authors.forename: Li Fan
authors.initials: LF
authors.lastname: Liang
authors.forename: Prabhu
authors.initials: P
authors.lastname: Padmanabhan
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D001616:beta-Galactosidase; D000252:Calcium-Transporting ATPases; D002118:Calcium