Beaudoin Marie-Soleil, Perry Christopher G R, Arkell Alicia M, Chabowski Adrian, Simpson Jeremy A, Wright David C, Holloway Graham P
Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada, M3J 1P3.
J Physiol. 2014 Jun 15;592(12):2519-33. doi: 10.1113/jphysiol.2013.270538. Epub 2014 Mar 17.
Alterations in lipid metabolism within the heart may have a causal role in the establishment of diabetic cardiomyopathy; however, this remains equivocal. Therefore, in the current study we determined cardiac mitochondrial bioenergetics in ZDF rats before overt type 2 diabetes and diabetic cardiomyopathy developed. In addition, we utilized resveratrol, a compound previously shown to improve, prevent or reverse cardiac dysfunction in high-fat-fed rodents, as a tool to potentially recover dysfunctions within mitochondria. Fasting blood glucose and invasive left ventricular haemodynamic analysis confirmed the absence of type 2 diabetes and diabetic cardiomyopathy. However, fibrosis was already increased (P < 0.05) ∼70% in ZDF rats at this early stage in disease progression. Assessments of mitochondrial ADP and pyruvate respiratory kinetics in permeabilized fibres from the left ventricle revealed normal electron transport chain function and content. In contrast, the apparent Km to palmitoyl-CoA (P-CoA) was increased (P < 0.05) ∼60%, which was associated with an accumulation of intracellular triacylgycerol, diacylglycerol and ceramide species. In addition, the capacity for mitochondrial reactive oxygen species emission was increased (P < 0.05) ∼3-fold in ZDF rats. The provision of resveratrol reduced fibrosis, P-CoA respiratory sensitivity, reactive lipid accumulation and mitochondrial reactive oxygen species emission rates. Altogether the current data support the supposition that a chronic dysfunction within mitochondrial lipid-supported bioenergetics contributes to the development of diabetic cardiomyopathy, as this was present before overt diabetes or cardiac dysfunction. In addition, we show that resveratrol supplementation prevents these changes, supporting the belief that resveratrol is a potent therapeutic approach for preventing diabetic cardiomyopathy.
心脏脂质代谢的改变可能在糖尿病性心肌病的发生中起因果作用；然而，这一点仍不明确。因此，在本研究中，我们在ZDF大鼠出现明显的2型糖尿病和糖尿病性心肌病之前，测定了其心脏线粒体生物能量学。此外，我们使用白藜芦醇，一种先前已证明可改善、预防或逆转高脂喂养啮齿动物心脏功能障碍的化合物，作为一种可能恢复线粒体功能障碍的工具。空腹血糖和有创左心室血流动力学分析证实不存在2型糖尿病和糖尿病性心肌病。然而，在疾病进展的这个早期阶段，ZDF大鼠的纤维化已经增加（P<0.05）约70%。对左心室透化纤维中线粒体ADP和丙酮酸呼吸动力学的评估显示电子传递链功能和含量正常。相比之下，对棕榈酰辅酶A（P-CoA） 的表观米氏常数增加了（P<0.05）约60%，这与细胞内甘油三酯、甘油二酯和神经酰胺的积累有关。此外，ZDF大鼠线粒体活性氧释放能力增加（P<0.05）约3倍。给予白藜芦醇可减少纤维化、P-CoA呼吸敏感性、活性脂质积累和线粒体活性氧释放率。总之，目前的数据支持这样一种假设，即线粒体脂质支持的生物能量学中的慢性功能障碍促成了糖尿病性心肌病的发展，因为这种功能障碍在明显的糖尿病或心脏功能障碍出现之前就已存在。此外，我们表明补充白藜芦醇可预防这些变化，支持了白藜芦醇是预防糖尿病性心肌病的有效治疗方法这一观点。
