Van Linthout Sophie, Spillmann Frank, Riad Alexander, Trimpert Christiane, Lievens Joke, Meloni Marco, Escher Felicitas, Filenberg Elena, Demir Okan, Li Jun, Shakibaei Mehdi, Schimke Ingolf, Staudt Alexander, Felix Stephan B, Schultheiss Heinz-Peter, De Geest Bart, Tschöpe Carsten
Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Circulation. 2008 Mar 25;117(12):1563-73. doi: 10.1161/CIRCULATIONAHA.107.710830. Epub 2008 Mar 10.
The hallmarks of diabetic cardiomyopathy are cardiac oxidative stress, intramyocardial inflammation, cardiac fibrosis, and cardiac apoptosis. Given the antioxidative, antiinflammatory, and antiapoptotic potential of high-density lipoprotein (HDL), we evaluated the hypothesis that increased HDL via gene transfer (GT) with human apolipoprotein (apo) A-I, the principal apolipoprotein of HDL, may reduce the development of diabetic cardiomyopathy.
Intravenous GT with 3x10(12) particles/kg of the E1E3E4-deleted vector Ad.hapoA-I, expressing human apoA-I, or Ad.Null, containing no expression cassette, was performed 5 days after streptozotocin (STZ) injection. Six weeks after apoA-I GT, HDL cholesterol levels were increased by 1.6-fold (P<0.001) compared with diabetic controls injected with the Ad.Null vector (STZ-Ad.Null). ApoA-I GT and HDL improved LV contractility in vivo and cardiomyocyte contractility ex vivo, respectively. Moreover, apoA-I GT was associated with decreased cardiac oxidative stress and reduced intramyocardial inflammation. In addition, compared with STZ-Ad.Null rats, cardiac fibrosis and glycogen accumulation were reduced by 1.7-fold and 3.1-fold, respectively (P<0.05). Caspase 3/7 activity was decreased 1.2-fold (P<0.05), and the ratio of Bcl-2 to Bax was upregulated 1.9-fold (P<0.005), translating to 2.1-fold (P<0.05) reduced total number of cardiomyocytes with apoptotic characteristics and 3.0-fold (P<0.005) reduced damaged endothelial cells compared with STZ-Ad.Null rats. HDL supplementation ex vivo reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold (P<0.005). The apoA-I GT-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and glycogen synthase kinase ratio, respectively (P<0.005).
ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.
糖尿病性心肌病的特征包括心脏氧化应激、心肌内炎症、心脏纤维化和心脏细胞凋亡。鉴于高密度脂蛋白（HDL）具有抗氧化、抗炎和抗细胞凋亡的潜力，我们评估了通过基因转移（GT）导入人载脂蛋白（apo）A-I（HDL的主要载脂蛋白）来增加HDL水平，可能会减轻糖尿病性心肌病发展的这一假设。
在注射链脲佐菌素（STZ）5天后，静脉注射3×10¹²颗粒/千克的缺失E1E3E4的载体Ad.hapoA-I（表达人apoA-I）或不含表达盒的Ad.Null。apoA-I基因转移6周后，与注射Ad.Null载体的糖尿病对照（STZ-Ad.Null）相比，HDL胆固醇水平增加了1.6倍（P<0.001）。apoA-I基因转移和HDL分别改善了体内左心室收缩力和体外心肌细胞收缩力。此外，apoA-I基因转移与心脏氧化应激降低和心肌内炎症减轻有关。另外，与STZ-Ad.Null大鼠相比，心脏纤维化和糖原积累分别减少了1.7倍和3.1倍（P<0.05）。半胱天冬酶3/7活性降低了1.2倍（P<0.05），Bcl-2与Bax的比值上调了1.9倍（P<0.005），与STZ-Ad.Null大鼠相比，具有凋亡特征的心肌细胞总数减少了2.1倍（P<0.05），受损内皮细胞减少了3.0倍（P<0.005）。体外补充HDL使高血糖诱导的心肌细胞凋亡减少了3.4倍（P<0.005）。apoA-I基因转移介导的保护作用分别与糖尿病下调后磷酸化Akt、内皮型一氧化氮合酶和糖原合酶激酶比值的1.6倍、1.6倍和2.4倍诱导有关（P<0.005）。
apoA-I基因转移减轻了链脲佐菌素诱导的糖尿病性心肌病的发展。
