Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Monash Centre of Cardiovascular Research and Education in therapeutics, Melbourne, Australia.
Monash Centre of Cardiovascular Research and Education in therapeutics, Melbourne, Australia; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Cell Signal. 2020 Aug;72:109629. doi: 10.1016/j.cellsig.2020.109629. Epub 2020 Apr 8.
Cardiac fibrosis and myocyte hypertrophy are hallmarks of the cardiac remodelling process in cardiomyopathies such as heart failure (HF). Dyslipidemia or dysregulation of lipids contribute to HF. The dysregulation of high density lipoproteins (HDL) could lead to altered levels of other lipid metabolites that are bound to it such as sphingosine-1- phosphate (S1P). Recently, it has been shown that S1P and its analogue dihydrosphingosine-1-phosphate (dhS1P) are bound to HDL in plasma. The effects of dhS1P on cardiac cells have been obscure. In this study, we show that extracellular dhS1P is able to increase collagen synthesis in neonatal rat cardiac fibroblasts (NCFs) and cause hypertrophy of neonatal cardiac myocytes (NCMs). The janus kinase/signal transducer and activator (JAK/STAT) signalling pathway was involved in the increased collagen synthesis by dhS1P, through sustained increase of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Extracellular dhS1P increased phosphorylation levels of STAT1 and STAT3 proteins, also caused an early increase in gene expression of transforming growth factor-β (TGFβ), and sustained increase in TIMP1. Inhibition of JAKs led to inhibition of TIMP1 and TGFβ gene and protein expression. We also show that dhS1P is able to cause NCM hypertrophy through S1P-receptor-1 (S1PR1) signalling which is opposite to that of its analogue, S1P. Taken together, our results show that dhS1P increases collagen synthesis in cardiac fibroblasts causing fibrosis through dhS1P-JAK/STAT-TIMP1 signalling.
心肌纤维化和心肌细胞肥大是心肌病（如心力衰竭）中心脏重构过程的标志。血脂异常或脂质失调导致心力衰竭。高密度脂蛋白（HDL）的失调可能导致与其结合的其他脂质代谢物的水平发生变化，如鞘氨醇-1-磷酸（S1P）。最近，已经表明 S1P 及其类似物二氢鞘氨醇-1-磷酸（dhS1P）在血浆中与 HDL 结合。dhS1P 对心脏细胞的影响尚不清楚。在这项研究中，我们表明细胞外 dhS1P 能够增加新生大鼠心肌成纤维细胞（NCFs）的胶原蛋白合成，并导致新生心肌细胞（NCMs）肥大。Janus 激酶/信号转导和转录激活因子（JAK/STAT）信号通路参与了 dhS1P 引起的胶原蛋白合成增加，通过持续增加基质金属蛋白酶组织抑制剂 1（TIMP1）。细胞外 dhS1P 增加了 STAT1 和 STAT3 蛋白的磷酸化水平，也导致转化生长因子-β（TGFβ）的基因表达早期增加，并持续增加 TIMP1。JAK 抑制剂导致 TIMP1 和 TGFβ 基因和蛋白表达的抑制。我们还表明，dhS1P 通过 S1P 受体-1（S1PR1）信号导致 NCM 肥大，这与它的类似物 S1P 相反。总之，我们的结果表明，dhS1P 通过 dhS1P-JAK/STAT-TIMP1 信号增加心肌成纤维细胞中的胶原蛋白合成，导致纤维化。
