Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.
Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.
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DOI：
10.3389/fcvm.2021.574708
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发表时间：
2021
影响因子：
3.6
通讯作者：
Johns RA
中科院分区：
文献类型：
--
作者：
Tao B;Kumar S;Gomez-Arroyo J;Fan C;Zhang A;Skinner J;Hunter E;Yamaji-Kegan K;Samad I;Hillel AT;Lin Q;Zhai W;Gao WD;Johns RA
心脏（右）衰竭是肺动脉高压患者最常见的死亡原因。虽然从历史上看，右心室负荷增加被认为是这类患者右心衰的主要原因，但最近的证据表明负荷无关因素可能起作用。在这里，我们验证了抵抗素样分子α (RELMα)的假设，它与肺动脉高压血管重塑的发病机制有关，也有助于心脏代谢重塑，导致心力衰竭。重组RELMα (rRELMα)通过Tet-On表达系统在T-REx 293细胞系中生成。用纯化的rRELMα以50 nM的剂量处理培养的新生大鼠心肌细胞24小时。处理后的心肌细胞过氧化物酶体增殖物激活受体γ辅助激活因子1α (PGC-1α)和调节线粒体脂肪酸代谢的转录因子PPARα和ERRα的mRNA和蛋白表达均下降，而编码糖酵解相关蛋白的基因显著上调。用微孔板细胞呼吸仪评估，rRELMα处理的心肌细胞也表现出基础呼吸、最大呼吸、备用呼吸量、atp连接的OCR和糖酵解增加。透射电镜显示rRELMα处理心肌细胞线粒体超微结构异常。我们的数据表明，RELMα通过下调PGC-1α/PPARα/ERRα轴的表达来影响心脏能量代谢和线粒体结构、生物发生和功能。
Heart (right) failure is the most frequent cause of death in patients with pulmonary arterial hypertension. Although historically, increased right ventricular afterload has been considered the main contributor to right heart failure in such patients, recent evidence has suggested a potential role of load-independent factors. Here, we tested the hypothesis that resistin–like molecule α (RELMα), which has been implicated in the pathogenesis of vascular remodeling in pulmonary artery hypertension, also contributes to cardiac metabolic remodeling, leading to heart failure. Recombinant RELMα (rRELMα) was generated via a Tet-On expression system in the T-REx 293 cell line. Cultured neonatal rat cardiomyocytes were treated with purified rRELMα for 24 h at a dose of 50 nM. Treated cardiomyocytes exhibited decreased mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and transcription factors PPARα and ERRα, which regulate mitochondrial fatty acid metabolism, whereas genes that encode for glycolysis-related proteins were significantly upregulated. Cardiomyocytes treated with rRELMα also exhibited a decreased basal respiration, maximal respiration, spare respiratory capacity, ATP-linked OCR, and increased glycolysis, as assessed with a microplate-based cellular respirometry apparatus. Transmission electron microscopy revealed abnormal mitochondrial ultrastructure in cardiomyocytes treated with rRELMα. Our data indicate that RELMα affects cardiac energy metabolism and mitochondrial structure, biogenesis, and function by downregulating the expression of the PGC-1α/PPARα/ERRα axis.