Liu Yao-Lung, Huang Chiu-Ching, Chang Chiz-Chung, Chou Che-Yi, Lin Shih-Yi, Wang I-Kuan, Hsieh Dennis Jine-Yuan, Jong Gwo-Ping, Huang Chih-Yang, Wang Chao-Min
Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC.
Cardiorenal Med. 2015 Apr;5(2):79-88. doi: 10.1159/000371454. Epub 2015 Jan 27.
BACKGROUND/AIMS: Numerous epidemiological studies have associated elevated serum phosphorus levels with cardiovascular disease and the risk of death in the general population as well as in chronic kidney disease (CKD) and dialysis patients. In this study, we explored whether elevated phosphate conditions induce cardiac hypertrophy and attempted to identify the molecular and cellular mechanisms in the hypertrophic response.
H9c2 myocardial cells were incubated in high-phosphate conditions to induce hypertrophy. Pathological hypertrophic responses were measured in terms of cell size, arrangement of actin filaments, and hypertrophy markers such as atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in myocardial cells. Several transcriptional factors involved in cardiac hypertrophy development were measured to investigate the molecular pathways involved in elevated phosphate-induced cardiac hypertrophy.
High-phosphate conditions induced cellular hypertrophy, marked by increased cell size, reorganization of actin filaments, and upregulation of both ANP and BNP in H9c2 cells. Both upstream calcineurin and downstream transcription factors, including GATA-4 and NFAT-3, were significantly increased under hyperphosphate conditions. Moreover, both MEK1/2 and ERK1/2 expression increased significantly, and cellular hypertrophy was markedly attenuated by U0126, an ERK1/2 inhibitor.
These results suggest that hyperphosphate conditions induce myocardial hypertrophy through the ERK signaling pathway in H9c2 cells. Our findings provide a link between the hyperphosphate-induced response and the ERK/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy. In view of the potent and selective activity of the ERK inhibitor U0126, this agent warrants further investigation as a candidate for preventing hyperphosphate-induced cardiac hypertrophy in CKD and dialysis patients.
背景/目的：众多流行病学研究已将血清磷水平升高与普通人群、慢性肾脏病（CKD）及透析患者的心血管疾病和死亡风险联系起来。在本研究中，我们探究了高磷状态是否会诱导心肌肥大，并试图确定肥大反应中的分子和细胞机制。
将H9c2心肌细胞置于高磷环境中以诱导肥大。通过测量细胞大小、肌动蛋白丝排列以及心肌细胞中的肥大标志物如心钠素（ANP）和B型利钠肽（BNP）来评估病理性肥大反应。检测参与心肌肥大发展的几种转录因子，以研究高磷诱导心肌肥大所涉及的分子途径。
高磷环境诱导了细胞肥大，其特征为H9c2细胞大小增加、肌动蛋白丝重排以及ANP和BNP均上调。在高磷条件下，上游钙调神经磷酸酶和下游转录因子（包括GATA-4和NFAT-3）均显著增加。此外，MEK1/2和ERK1/2的表达均显著增加，而ERK1/2抑制剂U0126可显著减轻细胞肥大。
这些结果表明，高磷环境通过ERK信号通路在H9c2细胞中诱导心肌肥大。我们的研究结果揭示了高磷诱导反应与介导心肌肥大发展的ERK/NFAT-3信号通路之间的联系。鉴于ERK抑制剂U0126具有强效和选择性活性，该药物作为预防CKD和透析患者高磷诱导心肌肥大的候选药物值得进一步研究。
