Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
Acta Physiol (Oxf). 2010 Sep;200(1):11-22. doi: 10.1111/j.1748-1716.2010.02102.x. Epub 2010 Feb 17.
To identify the initial alterations in myocardial tissue associated with the early signs of diabetic cardiac haemodynamic dysfunction, we monitored changes in cardiac function, structural remodelling and gene expression in hearts of type 2 diabetic db/db mice.
Cardiac dimensions and function were determined echocardiographically at 8, 12, 16 and 18 weeks of age. Left ventricular pressure characteristics were measured at 18 weeks under baseline conditions and upon dobutamine infusion.
The db/db mice were severely diabetic already at 8 weeks after birth, showing elevated fasting blood glucose levels and albuminuria. Nevertheless, echocardiography revealed no significant changes in cardiac function up to 18 weeks of age. At 18 weeks of age, left ventricular pressure characteristics were not significantly different at baseline between diabetic and control mice. However, dobutamine stress test revealed significantly attenuated cardiac inotropic and lusitropic responses in db/db mice. Post-mortem cardiac tissue analyses showed minor structural remodelling and no significant changes in gene expression levels of the sarcoplasmic reticulum calcium ATPase (SERCA2a) or beta1-adrenoceptor (beta1-AR). Moreover, the phosphorylation state of known contractile protein targets of protein kinase A (PKA) was not altered, indicating unaffected cardiac beta-adrenergic signalling activity in diabetic animals. By contrast, the substantially increased expression of uncoupling protein-3 (UCP3) and angiopoietin-like-4 (Angptl4), along with decreased phosphorylation of AMP-activated protein kinase (AMPK) in the diabetic heart, is indicative of marked changes in cardiac metabolism.
db/db mice show impaired cardiac functional reserve capacity during maximal beta-adrenergic stimulation which is associated with unfavourable changes in cardiac energy metabolism.
为了确定与糖尿病心脏血流动力学功能障碍早期迹象相关的心肌组织的初始改变，我们监测了 2 型糖尿病 db/db 小鼠心脏功能、结构重塑和基因表达的变化。
在 8、12、16 和 18 周龄时通过超声心动图监测心脏尺寸和功能。在 18 周龄时，在基础条件和多巴酚丁胺输注下测量左心室压力特征。
db/db 小鼠在出生后 8 周就已经患有严重的糖尿病，表现为空腹血糖水平升高和白蛋白尿。尽管如此，超声心动图显示在 18 周龄之前心脏功能没有明显变化。在 18 周龄时，糖尿病和对照组小鼠的基础状态下左心室压力特征没有显著差异。然而，多巴酚丁胺应激试验显示 db/db 小鼠的心脏变力和舒张反应明显减弱。死后心脏组织分析显示结构重塑轻微，肌浆网钙 ATP 酶（SERCA2a）或β1-肾上腺素能受体（β1-AR）的基因表达水平没有显著变化。此外，蛋白激酶 A（PKA）的已知收缩蛋白靶标的磷酸化状态没有改变，表明糖尿病动物的心脏β-肾上腺素能信号活性未受影响。相比之下，在糖尿病心脏中，解偶联蛋白 3（UCP3）和血管生成素样蛋白 4（Angptl4）的表达显著增加，同时 AMP 激活的蛋白激酶（AMPK）的磷酸化减少，表明心脏代谢发生了显著变化。
db/db 小鼠在最大β-肾上腺素能刺激时表现出心脏功能储备能力受损，这与心脏能量代谢的不利变化有关。
