Deluyker Dorien, Evens Lize, Beliën Hanne, Bito Virginie
Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
Exp Physiol. 2019 Jul;104(7):997-1003. doi: 10.1113/EP087127. Epub 2019 May 4.
What is the central question of this study? Does acute exposure to high molecular weight advanced glycation end products (HMW-AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance? Ventricular cardiomyocytes display reduced Ca influx, resulting in reduced contractile capacity, after acute exposure to HMW-AGEs, independent of activation of their receptor. Given that HMW-AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds.
Sustained elevated levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW-AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre-incubated with or without an anti-RAGE antibody. Unloaded cell shortening and L-type Ca current amplitude were evaluated in the presence or absence of HMW-AGEs (200 μg ml ). Expression of RAGE, c-Jun N-terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW-AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca influx. These alterations were also observed in cardiomyocytes pre-incubated with anti-RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW-AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.
本研究的核心问题是什么？急性暴露于高分子量晚期糖基化终产物（HMW-AGEs）是否会改变心肌细胞的收缩功能？主要发现及其重要性是什么？急性暴露于HMW-AGEs后，心室心肌细胞的钙内流减少，导致收缩能力下降，且与它们受体的激活无关。鉴于HMW-AGEs在我们的西方饮食中大量存在，对于这些化合物，应该更好地了解其潜在机制，尤其是在已经表现出心脏功能改变的患者中。
已知高分子量晚期糖基化终产物（HMW-AGEs）持续升高会促进心脏功能障碍。最近的数据表明，在氧化应激增加的情况下会出现AGEs急性升高。这种升高是否会对心脏功能产生有害影响仍不清楚。在本研究中，我们调查了急性暴露于HMW-AGEs是否通过激活其受体（RAGE）信号通路影响心肌细胞功能。通过主动脉逆行灌注酶解从成年雄性大鼠左心室获取单个心肌细胞。在预先用或不用抗RAGE抗体孵育的心肌细胞中进行功能实验。在有或没有HMW-AGEs（200μg/ml）的情况下评估无负荷细胞缩短和L型钙电流幅度。通过蛋白质印迹法评估RAGE、c-Jun氨基末端激酶（JNK）和磷酸化JNK（pJNK）的表达。实验在室温下进行。施加HMW-AGEs 4分钟后，无负荷细胞缩短明显减少。这种收缩功能受损与钙内流减少有关。在用抗RAGE抗体预先孵育的心肌细胞中也观察到了这些变化。我们的研究表明，急性暴露于高水平的HMW-AGEs会导致直接且不可逆的心肌细胞功能障碍，与RAGE激活无关。
