Abstract:
Methylglyoxal (MGO) is an endogenous, highly reactive dicarbonyl metabolite generated under hyperglycaemic conditions. MGO plays a role in developing pathophysiological conditions, including diabetic cardiomyopathy. However, the mechanisms involved and the molecular targets of MGO in the heart have not been elucidated. In this work, we studied the exposure-related effects of MGO on cardiac function in an isolated perfused rat heart ex vivo model. The effect of MGO on calcium homeostasis in cardiomyocytes was studied in vitro by the fluorescence indicator of intracellular calcium Fluo-4. We demonstrated that MGO induced cardiac dysfunction, both in contractility and diastolic function. In rat heart, the effects of MGO treatment were significantly limited by aminoguanidine, a scavenger of MGO, ruthenium red, a general cation channel blocker, and verapamil, an L-type voltage-dependent calcium channel blocker, demonstrating that this dysfunction involved alteration of calcium regulation. MGO induced a significant concentration-dependent increase of intracellular calcium in neonatal rat cardiomyocytes, which was limited by aminoguanidine and verapamil. These results suggest that the functionality of various calcium channels is altered by MGO, particularly the L-type calcium channel, thus explaining its cardiac toxicity. Therefore, MGO could participate in the development of diabetic cardiomyopathy through its impact on calcium homeostasis in cardiac cells.
摘要:
甲基乙二醛(MGO)是一种内源性,在高血糖条件下产生的高反应性二羰基代谢物。MGO在发展病理生理条件中发挥作用,包括糖尿病性心肌病.然而,MGO在心脏中的作用机制和分子靶标尚未阐明。在这项工作中,我们在离体灌流大鼠心脏模型中研究了MGO暴露对心脏功能的影响.通过细胞内钙Fluo-4的荧光指示剂研究了MGO对心肌细胞钙稳态的影响。我们证明了MGO诱导的心功能不全,收缩和舒张功能。在老鼠的心脏,MGO治疗的效果受到氨基胍的显著限制,MGO的清道夫,钌红,一般的阳离子通道阻断剂,和维拉帕米,L型电压依赖性钙通道阻滞剂,证明这种功能障碍涉及钙调节的改变。MGO诱导新生大鼠心肌细胞内钙的浓度依赖性显著增加,这是由氨基胍和维拉帕米限制。这些结果表明,MGO改变了各种钙通道的功能,特别是L型钙通道,从而解释了它的心脏毒性。因此,MGO可能通过影响心肌细胞钙稳态参与糖尿病心肌病的发生发展。