Connelly K A, Kelly D J, Zhang Y, Prior D L, Martin J, Cox A J, Thai K, Feneley M P, Tsoporis J, White K E, Krum H, Gilbert R E
University of Melbourne Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Cardiovasc Res. 2007 Nov 1;76(2):280-91. doi: 10.1016/j.cardiores.2007.06.022. Epub 2007 Jun 29.
Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model.
Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition.
Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats.
These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.
尽管左心室收缩功能保留，但糖尿病性心肌病仍是心力衰竭日益常见的病因。鉴于血管紧张素II在人类糖尿病性心肌病中过度表达，我们推测在啮齿动物模型中，高血糖与增强的组织肾素-血管紧张素系统相结合会导致舒张功能障碍并伴有不良重塑。
将纯合子（mRen-2）27大鼠和非转基因Sprague Dawley（SD）大鼠随机分为接受链脲佐菌素（糖尿病组）或赋形剂（非糖尿病组），并随访6周。在采集组织之前，对动物进行压力-容积环采集。
糖尿病Ren-2大鼠舒张期的主动和被动阶段均出现功能障碍，同时伴有肌浆网钙ATP酶2a（SERCA-2a ATPase）和受磷蛋白减少以及胎儿基因程序激活。Ren-2大鼠糖尿病性心肌病的结构特征包括间质纤维化、心肌细胞肥大和凋亡，同时转化生长因子-β的活性增加（与非糖尿病Ren-2大鼠相比，所有参数p<0.01）。在非转基因SD糖尿病大鼠中未观察到明显的功能或结构紊乱。
这些发现表明，增强的组织肾素-血管紧张素系统与高血糖相结合会导致糖尿病性心肌病的发生。纤维化和心肌细胞肥大是该模型的一个显著特征，可能是糖尿病状态激活促硬化细胞因子转化生长因子-β的结果。
