Lee Tsung-Ming, Lin Shinn-Zong, Chang Nen-Chung
Department of Medicine, Cardiology Section, An Nan Hospital, China Medical University, Tainan, Taiwan.
Department of Medicine, China Medical University, Taichung, Taiwan.
Biosci Rep. 2017 Mar 27;37(2). doi: 10.1042/BSR20160257. Print 2017 Apr 28.
Activation of phosphoinositide 3-kinase (PI3K)/Akt signalling is the molecular pathway driving physiological hypertrophy. As lithium, a PI3K agonist, is highly toxic at regular doses, we assessed the effect of lithium at a lower dose on ventricular hypertrophy after myocardial infarction (MI). Male Wistar rats after induction of MI were randomized to either vehicle or lithium (1 mmol/kg per day) for 4 weeks. The dose of lithium led to a mean serum level of 0.39 mM, substantially lower than the therapeutic concentrations (0.8-1.2 mM). Infarction in the vehicle was characterized by pathological hypertrophy in the remote zone; histologically, by increased cardiomyocyte sizes, interstitial fibrosis and left ventricular dilatation; functionally, by impaired cardiac contractility; and molecularly, by an increase of p-extracellular-signal-regulated kinase (ERK) levels, nuclear factor of activated T cells (NFAT) activity, expression and foetal gene expressions. Lithium administration mitigated pathological remodelling. Furthermore, lithium caused increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 (p-4E-BP1), the downstream target of mammalian target of rapamycin (mTOR). Blockade of the Akt and mTOR signalling pathway with deguelin and rapamycin resulted in markedly diminished levels of p-4E-BP1, but not ERK. The present study demonstrated that chronic lithium treatment at low doses mitigates pathological hypertrophy through an Akt/mTOR dependent pathway.
磷酸肌醇3激酶（PI3K）/Akt信号通路的激活是驱动生理性肥大的分子途径。由于锂作为一种PI3K激动剂，常规剂量下具有高毒性，我们评估了低剂量锂对心肌梗死后心室肥大的影响。诱导心肌梗死后的雄性Wistar大鼠被随机分为接受载体或锂（每天1 mmol/kg）治疗4周。锂的剂量导致平均血清水平为0.39 mM，显著低于治疗浓度（0.8 - 1.2 mM）。接受载体治疗的梗死表现为远隔区的病理性肥大；组织学上，表现为心肌细胞大小增加、间质纤维化和左心室扩张；功能上，表现为心脏收缩力受损；分子水平上，表现为磷酸化细胞外信号调节激酶（ERK）水平增加、活化T细胞核因子（NFAT）活性、表达以及胎儿基因表达增加。锂的给药减轻了病理性重塑。此外，锂导致真核起始因子4E结合蛋白1（p - 4E - BP1）磷酸化增加，p - 4E - BP1是雷帕霉素靶蛋白（mTOR）的下游靶点。用鱼藤素和雷帕霉素阻断Akt和mTOR信号通路导致p - 4E - BP1水平显著降低，但ERK水平未降低。本研究表明，低剂量慢性锂治疗通过Akt/mTOR依赖途径减轻病理性肥大。
