Yang Jinjing, Xu Jiyao, Han Xuebin, Wang Hao, Zhang Yuean, Dong Jin, Deng Yongzhi, Wang Jingping
Department of Cardiology, Shanxi Cardiovascular Disease Hospital, Taiyuan, China.
Shanxi Cardiovascular Disease Institute, Taiyuan, China.
Front Physiol. 2018 Sep 18;9:1315. doi: 10.3389/fphys.2018.01315. eCollection 2018.
Lysophosphatidic acid (LPA), as a phospholipid signal molecule, participates in the regulation of various biological functions. Our previous study demonstrated that LPA induces cardiomyocyte hypertrophy ; however, the functional role of LPA in the post-infarct heart remains unknown. Growing evidence has demonstrated that autophagy is involved in regulation of cardiac hypertrophy. The aim of the current work was to investigate the effects of LPA on cardiac function and hypertrophy during myocardial infarction (MI) and determine the regulatory role of autophagy in LPA-induced cardiomyocyte hypertrophy. experiments were conducted in Sprague-Dawley rats subjected to MI surgery or a sham operation, and rats with MI were assigned to receive an intraperitoneal injection of LPA (1 mg/kg) or vehicle for 5 weeks. The experiments were conducted in H9C2 cardiomyoblasts. LPA treatment aggravated cardiac dysfunction, increased cardiac hypertrophy, and reduced autophagy after MI . LPA suppressed autophagy activation, as indicated by a decreased LC3II-to-LC3I ratio, increased p62 expression, and reduced autophagosome formation . Rapamycin, an autophagy enhancer, attenuated LPA-induced autophagy inhibition and H9C2 cardiomyoblast hypertrophy, while autophagy inhibition with Beclin1 siRNA did not further enhance the hypertrophic response in LPA-treated cardiomyocytes. Moreover, we demonstrated that LPA suppressed autophagy through the AKT/mTOR signaling pathway because mTOR and PI3K inhibitors significantly prevented LPA-induced mTOR phosphorylation and autophagy inhibition. In addition, we found that knockdown of LPA3 alleviated LPA-mediated autophagy suppression in H9C2 cardiomyoblasts, suggesting that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways. These findings suggest that LPA plays an important role in mediating cardiac dysfunction and hypertrophy after a MI, and that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways to induce cardiomyocyte hypertrophy.
溶血磷脂酸（LPA）作为一种磷脂信号分子，参与多种生物学功能的调节。我们之前的研究表明，LPA可诱导心肌细胞肥大；然而，LPA在心肌梗死后心脏中的功能作用仍不清楚。越来越多的证据表明，自噬参与心脏肥大的调节。本研究的目的是探讨LPA在心肌梗死（MI）期间对心脏功能和肥大的影响，并确定自噬在LPA诱导的心肌细胞肥大中的调节作用。实验在接受MI手术或假手术的Sprague-Dawley大鼠中进行，MI大鼠被分为腹腔注射LPA（1mg/kg）或溶剂对照组，持续5周。实验也在H9C2心肌成纤维细胞中进行。LPA处理加重了MI后的心脏功能障碍，增加了心脏肥大，并减少了自噬。LPA抑制自噬激活，表现为LC3II与LC3I比值降低、p62表达增加和自噬体形成减少。自噬增强剂雷帕霉素减轻了LPA诱导的自噬抑制和H9C2心肌成纤维细胞肥大，而用Beclin1 siRNA抑制自噬并未进一步增强LPA处理的心肌细胞的肥大反应。此外，我们证明LPA通过AKT/mTOR信号通路抑制自噬，因为mTOR和PI3K抑制剂显著阻止了LPA诱导的mTOR磷酸化和自噬抑制。此外，我们发现敲低LPA3可减轻LPA介导的H9C2心肌成纤维细胞自噬抑制，提示LPA通过激活LPA3和AKT/mTOR通路抑制自噬。这些发现表明，LPA在介导MI后心脏功能障碍和肥大中起重要作用，并且LPA通过激活LPA3和AKT/mTOR通路抑制自噬以诱导心肌细胞肥大。
