Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN 55812, USA.
Biochem Pharmacol. 2020 Apr;174:113832. doi: 10.1016/j.bcp.2020.113832. Epub 2020 Feb 6.
Cardiorenal syndrome type-3 (CRS-3) is characterized by acute cardiac injury induced by acute kidney injury. Here, we investigated the causes of CRS-3 by analyzing cardiac function after renal ischemia-reperfusion injury (IRI) using echocardiography and evaluation of pro-inflammatory markers, calcium balance, mitochondrial function, and cardiomyocyte death. Our results show that renal IRI reduces cardiac diastolic function associated with cardiomyocyte death and inflammatory responses. Renal IRI also disrupts cardiomyocyte energy metabolism, induces calcium overload, and impairs mitochondrial function, as evidenced by reduced mitochondrial membrane potential and increased mitochondrial fission. Further, renal IRI induces phosphorylation of inositol 1,4,5-trisphosphate receptor (IP3R) and expression of mitochondrial calcium uniporter (MCU), resulting in cytoplasmic calcium overload and mitochondrial calcium accumulation. Pretreatment with melatonin attenuates renal IRI-mediated cardiac damage by maintaining myocardial diastolic function and reducing cardiomyocyte death. Melatonin also inhibits IP3R phosphorylation and MCU expression, thereby alleviating cytoplasmic and mitochondrial calcium overload. Blockade of IP3R has similar cardioprotective effects, whereas MCU activation abrogates the melatonin-mediated cardioprotection. These results show that the negative effects of renal IRI on myocardial viability and cardiac function are caused by induced IP3R phosphorylation, MCU upregulation, and calcium overload. Melatonin protects cardiac function against CRS-3 by suppressing IP3R-MCU signaling.
心脏肾综合征 3 型（CRS-3）的特征是急性肾损伤引起的急性心脏损伤。在这里，我们通过使用超声心动图评估促炎标志物、钙平衡、线粒体功能和心肌细胞死亡来研究肾缺血再灌注损伤（IRI）后 CRS-3 的原因。我们的结果表明，肾 IRI 降低了与心肌细胞死亡和炎症反应相关的心脏舒张功能。肾 IRI 还破坏了心肌细胞的能量代谢，导致钙超载，并损害了线粒体功能，这表现为线粒体膜电位降低和线粒体分裂增加。此外，肾 IRI 诱导肌醇 1,4,5-三磷酸受体（IP3R）磷酸化和线粒体钙单向转运体（MCU）的表达，导致细胞质钙超载和线粒体钙积累。褪黑素预处理通过维持心肌舒张功能和减少心肌细胞死亡来减轻肾 IRI 介导的心脏损伤。褪黑素还抑制 IP3R 磷酸化和 MCU 表达，从而减轻细胞质和线粒体钙超载。IP3R 阻断具有相似的心脏保护作用，而 MCU 激活则消除了褪黑素介导的心脏保护作用。这些结果表明，肾 IRI 对心肌活力和心功能的负面影响是由诱导的 IP3R 磷酸化、MCU 上调和钙超载引起的。褪黑素通过抑制 IP3R-MCU 信号通路来保护心脏功能免受 CRS-3 的影响。
