Related Experiment Video
Updated: Mar 8, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Effect of lithium on ventricular remodelling in infarcted rats via the Akt/mTOR signalling pathways
Tsung-Ming Lee1,2,3,4, Shinn-Zong Lin5, Nen-Chung Chang6,7
1Department of Medicine, Cardiology Section, An Nan Hospital, China Medical University, Tainan, Taiwan.
Insights
Low-dose lithium mitigates cardiac hypertrophy after myocardial infarction by activating the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, offering a potential therapeutic strategy.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Physiological hypertrophy is driven by phosphoinositide 3-kinase (PI3K)/Akt signaling.
- Lithium, a PI3K agonist, is toxic at therapeutic doses, necessitating investigation of lower doses for cardiac applications.
Purpose of the Study:
- To evaluate the effects of low-dose lithium on ventricular hypertrophy following myocardial infarction (MI).
- To elucidate the molecular pathways involved in lithium's cardioprotective effects.
Main Methods:
- Male Wistar rats with induced MI were treated with vehicle or low-dose lithium (1 mmol/kg/day) for 4 weeks.
- Cardiac structure, function, and molecular markers (p-ERK, NFAT, GATA4, p-4E-BP1) were assessed.
- The role of Akt and mTOR pathways was investigated using deguelin and rapamycin.
Main Results:
- Lithium treatment mitigated pathological cardiac remodeling, including cardiomyocyte size, fibrosis, and left ventricular dilatation.
- Lithium increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 (p-4E-BP1), a downstream target of mammalian target of rapamycin (mTOR).
- Inhibition of Akt and mTOR pathways reduced p-4E-BP1 levels, confirming pathway involvement.
Conclusions:
- Chronic low-dose lithium administration effectively reduces pathological hypertrophy post-MI.
- The cardioprotective effects of lithium are mediated through the Akt/mTOR signaling pathway.
Abstract:
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, GATA4 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.
