Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function
Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function
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DOI：
10.1152/ajpheart.00452.2009
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发表时间：
2009-12-01
影响因子：
4.8
通讯作者：
Kassiri, Zamaneh
中科院分区：
文献类型：
--
作者：
Basu, Ratnadeep;Oudit, Gavin Y.;Kassiri, Zamaneh
杨文，王晓，张立，王晓，王晓.秋田（Ins 2（WT/C96 Y））小鼠模型中的1型糖尿病性心肌病的特征为脂毒性和舒张功能障碍，同时保留收缩功能。美国生理学杂志心脏循环生理学297：H2096-H2108，2009年。首次发表于2009年10月2日; doi：10.1152/ajpheart.00452.2009。糖尿病性心肌病是舒张性和收缩性心力衰竭的重要原因。我们研究了秋田（Ins 2（WT/C96 Y））小鼠心肌病的性质和机制，这是一种遗传性非肥胖1型糖尿病模型，重现了人类1型糖尿病。使用超声心动图和组织多普勒成像、体内血液动力学测量以及离体工作心脏制备，在雄性Ins 2（WT/C96 Y）及其同窝对照（Ins 2（WT/WT））小鼠中评价心脏功能。在3月龄和6月龄时，与Ins 2（WT/WT）小鼠相比，Ins 2（WT/C96 Y）小鼠表现出保留的心脏收缩功能，如通过射血分数、缩短分数、左心室（LV）收缩末期压力和体内LV压力的最大增加速率、心脏作功、心脏功率和离体心率-压力乘积所评价的。尽管收缩功能未改变，但与Ins 2（WT/WT）小鼠相比，Ins 2（WT/C96 Y）小鼠在3月龄和6月龄时表现出显著和进行性舒张功能障碍，这通过组织和脉冲多普勒成像（E波速度、等容舒张时间）和体内血液动力学测量（LV舒张末期压、LV舒张时间常数和LV压力最大下降速率）进行评估。我们在Ins 2（WT/C96 Y）心肌中未发现心肌肥大或纤维化的证据。与缺乏纤维化一致，在这些心脏中，前胶原-α I型、前胶原-α III型和纤连蛋白的表达没有增加。Ins 2 WT/C96 Y心脏显示肌浆网Ca 2 +-ATP酶2a（心脏肌浆网Ca 2+泵）水平显著降低，β-肌球蛋白重链亚型升高，长链脂肪酸和三酰甘油增加，有脂毒性证据，心肌中神经酰胺、二酰甘油和脂质沉积显著增加。与代谢紊乱一致，Ins 2（WT/C96 Y）心脏中葡萄糖氧化转换为脂肪酸氧化，线粒体长链酰基辅酶A脱氢酶和丙酮酸脱氢酶激酶亚型4的表达增加。胰岛素治疗逆转了舒张功能障碍，B型利钠肽和β-肌球蛋白重链升高，肌浆网Ca 2 +-ATP酶2a水平降低，心脏脂毒性消失。我们的结论是，早期1型糖尿病心肌病的特点是舒张功能障碍与脂毒性心肌病与保存的收缩功能，在没有间质纤维化和肥大。
Basu R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z. Type 1 diabetic cardiomyopathy in the Akita (Ins2(WT/C96Y)) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 297: H2096-H2108, 2009. First published October 2, 2009; doi: 10.1152/ajpheart.00452.2009.-Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita (Ins2(WT/C96Y)) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins2(WT/C96Y) and their littermate control (Ins2(WT/WT)) mice using echocardiography and tissue Doppler imaging, in vivo hemodynamic measurements, as well as ex vivo working heart preparation. At 3 and 6 mo of age, Ins2(WT/C96Y) mice exhibited preserved cardiac systolic function compared with Ins2(WT/WT) mice, as evaluated by ejection fraction, fractional shortening, left ventricular (LV) end-systolic pressure and maximum rate of increase in LV pressure in vivo, cardiac work, cardiac power, and rate-pressure product ex vivo. Despite the unaltered systolic function, Ins2(WT/C96Y) mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins2(WT/WT) mice as assessed by tissue and pulse Doppler imaging (E-wave velocity, isovolumetric relaxation time) and by in vivo hemodynamic measurements (LV end-diastolic pressure, time constant of LV relaxation, and maximum rate of decrease in LV pressure). We found no evidence of myocardial hypertrophy or fibrosis in the Ins2(WT/C96Y) myocardium. Consistent with the lack of fibrosis, expression of procollagen-alpha type I, procollagen-alpha type III, and fibronectin were not increased in these hearts. Ins2WT/C96Y hearts showed significantly reduced sarcoplasmic reticulum Ca2+-ATPase 2a (cardiac sarcoplasmic reticulum Ca2+ pump) levels, elevated beta-myosin heavy chain isoform, increased long-chain fatty acids, and triacylglycerol with evidence of lipotoxicity, as indicated by a significant rise in ceramide, diacylglycerol, and lipid deposits in the myocardium. Consistent with metabolic perturbation, and a switch to fatty acid oxidation from glucose oxidation in Ins2(WT/C96Y) hearts, expression of mitochondrial long-chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase isoform 4 were increased. Insulin treatment reversed the diastolic dysfunction, the elevated B-type natriuretic peptide and beta-myosin heavy chain, and the reduced sarcoplasmic reticulum Ca2+-ATPase 2a levels with abolition of cardiac lipotoxicity. We conclude that early type 1 diabetic cardiomyopathy is characterized by diastolic dysfunction associated with lipotoxic cardiomyopathy with preserved systolic function in the absence of interstitial fibrosis and hypertrophy.