Sakata Susumu, Lebeche Djamel, Sakata Yuri, Sakata Naoya, Chemaly Elie R, Liang Li Fan, Padmanabhan Prabhu, Konishi Noboru, Takaki Miyako, del Monte Federica, Hajjar Roger J
Cardiovascular Research Center, Cardiology Laboratory of Integrative Physiology & Imaging, Massachusetts General Hospital, 149 13th Street, CNY-4, Charlestown, MA 02129, USA.
Mol Ther. 2006 May;13(5):987-96. doi: 10.1016/j.ymthe.2006.01.002. Epub 2006 Feb 24.
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.
大冢-长-埃文斯-德岛肥胖大鼠代表了一种自发性非胰岛素依赖型II型糖尿病（DM）模型，其特征为舒张功能障碍，并与钙处理异常及肌浆网Ca2+-ATP酶（SERCA2a）表达降低有关。本研究的目的是检验SERCA2a基因转移能否恢复该模型中的能量缺乏和左心室（LV）功能。将糖尿病大鼠随机分为三组，分别接受携带SERCA2a基因的腺病毒（DM + Ad.SERCA2a）、β-半乳糖苷酶基因的腺病毒（DM + Ad.βGal）或生理盐水（DM + 生理盐水）。感染3天后，在交叉循环心脏标本中测量左心室机械能量功能。与非糖尿病组（舒张末压0.1ml球囊内水时为12mmHg）相比，糖尿病组在球囊内水为0.1ml时收缩末压较低，舒张末压较高（22mmHg）。然而，在DM + Ad.SERCA2a组中，收缩末压0.1ml球囊内水时升高至200mmHg以上，舒张末压0.1ml球囊内水时降至7mmHg。DM + Ad.SERCA2a组左心室舒张速率较快，而其他糖尿病组较慢。所有组之间每搏心脏耗氧量与收缩压-容积面积的关系无差异。最后，糖尿病组左心室收缩的氧耗约为正常组的三倍。在DM + Ad.SERCA2a组中，氧耗降至对照水平，但在DM + Ad.βGal/DM + 生理盐水组中仍保持较高水平。在糖尿病性心力衰竭的心脏中，高氧耗表明能量浪费，这导致了糖尿病性心肌病中观察到的收缩功能障碍。SERCA2a基因转移将这种低效的能量利用转变为更有效的状态，并将收缩和舒张功能恢复正常。
