Valerenic acid attenuates pathological myocardial hypertrophy by promoting the utilization of multiple substrates in the mitochondrial energy metabolism
Academic Background
Pathological Myocardial Hypertrophy (PMH) is an adaptive response of the heart under various pathological stimuli, but its long-term development ultimately leads to Heart Failure (HF). Although some understanding of the pathogenesis of PMH has been established, its mortality rate remains high, and there is an urgent need for new therapeutic targets or strategies to prevent HF. Energy metabolism disorder is considered one of the main triggers of PMH, and pharmacological modulation of metabolism is seen as a novel treatment approach aimed at improving cardiac efficiency, reducing energy deficits, and enhancing the function of failing hearts.
In cardiac energy metabolism, mitochondrial oxidative phosphorylation is the primary source of ATP to sustain cardiac contraction. Fatty acids (FAs) are the most utilized substrate by the heart, providing 70% of its ATP demand. However, during the progression of PMH, an imbalance between energy supply and demand occurs, characterized by reduced fatty acid oxidation (FAO) and enhanced glycolysis. Additionally, recent studies have shown that the Pyruvate-Lactate Axis plays a crucial role in the progression of PMH. Reduced pyruvate oxidation and excessive lactate efflux exacerbate PMH. Therefore, improving myocardial utilization of multiple substrates may help slow the progression of HF.
Peroxisome Proliferator-Activated Receptor-α (PPARα) is a nuclear transcription factor that is considered a key regulator of energy metabolism and a potential therapeutic target for HF. PPARα directly regulates the expression of genes involved in fatty acid transport and mitochondrial fatty acid oxidation in cardiomyocytes. Furthermore, PPARα can negatively regulate glycolysis and downregulate glycolysis-related genes. Currently, PPARα agonists (such as fibrates) are used to treat hypercholesterolemia and hypertriglyceridemia, but their monotherapy may lead to a series of side effects, including gastrointestinal reactions, sleep disorders, and muscle pain. Therefore, developing safer PPARα agonists is of great significance.
Valerenic Acid (VA) is the main active component of Valeriana Officinalis L. and has been shown to have potential in regulating the cardiovascular system. Previous studies have demonstrated that valerian extract can improve myocardial ischemia-reperfusion injury by inhibiting lipid peroxidation and reduce the risk of arrhythmias induced by heart failure. Additionally, VA has hypotensive effects, but its therapeutic effects on PMH and its mechanisms remain unclear. Based on this, this study aims to explore the protective effects of VA on PMH and its underlying mechanisms.
Source of the Paper
This study was conducted by a research team from Beijing University of Chinese Medicine, with Tiantian Liu, Xu Chen, and Qianbin Sun as the primary authors. The paper was published in Journal of Advanced Research (Volume 68, Pages 241-256) in 2025. The research was supported by the National Natural Science Foundation of China (Grant Numbers: 82222075, 82374420, 82174364, 82174215).
Research Process and Results
1. VA’s Alleviation of ISO-Induced PMH
The study first constructed a Isoproterenol (ISO)-induced mouse model of PMH. The mice were divided into a sham group (Sham), model group (ISO), low-dose VA group (0.5 mg/kg), high-dose VA group (2 mg/kg), and a positive control group treated with fenofibrate. Cardiac function was assessed using echocardiography, which showed that both VA and fenofibrate significantly improved ISO-induced cardiac hypertrophy and functional impairment (P < 0.05). Simultaneously, VA treatment significantly reduced ISO-induced cardiomyocyte hypertrophy and myocardial fibrosis.
In cellular experiments, the study used an ISO-induced H9c2 cardiomyocyte hypertrophy model and found that VA at concentrations of 1-10 μM significantly inhibited ISO-induced cell hypertrophy and reduced the expression of hypertrophic markers (ANP, BNP, MYH7).
2. VA Regulates Energy Metabolism via PPARα Pathway
Electron microscopy observations revealed that ISO stimulation caused structural damage to mitochondria in cardiomyocytes, and VA treatment significantly improved mitochondrial structure and reduced lipid droplet accumulation. VA also significantly increased ATP content and reduced plasma levels of non-esterified fatty acids (NEFA), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Additionally, VA inhibited ISO-induced glycolysis and lowered lactate levels.
Network pharmacology experiments indicated that the PPAR signaling pathway might be the key pathway through which VA exerts its anti-hypertrophic effects. VA significantly upregulated PPARα and its downstream fatty acid oxidation-related genes (such as CD36, CPT1A, EHHAHD), while suppressing glycolysis-related genes (such as ENO1, PDK4). Furthermore, VA alleviated PMH by inhibiting inflammatory factors (e.g., IL-6, IL-1β, TNF-α).
3. VA Acts as a Direct PPARα Activator
Through molecular dynamics (MD) simulations and surface plasmon resonance (SPR) experiments, the study found that VA could bind to the F273 site of PPARα, with a KD value of 5 × 10⁻⁷ M, indicating that VA may act as a direct ligand for PPARα.
4. VA Modulates the Pyruvate-Lactate Axis
The study found that PPARα knockdown (si-PPARα) significantly increased lactate content in H9c2 cells, while VA treatment significantly reduced lactate levels and promoted pyruvate oxidation. Additionally, VA inhibited the expression of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4), further improving the balance of the pyruvate-lactate axis.
Conclusion and Significance
This study demonstrates that VA alleviates ISO-induced pathological myocardial hypertrophy by activating the PPARα pathway, promoting fatty acid oxidation, inhibiting glycolysis, and improving mitochondrial energy metabolism. VA, as a novel PPARα agonist, holds potential therapeutic value for PMH and HF. Moreover, VA modulates the pyruvate-lactate axis, promoting the oxidative utilization of pyruvate, providing new insights into the treatment of cardiac energy metabolism disorders.
Research Highlights
- First Discovery of VA Alleviating PMH via PPARα Activation: VA directly binds to PPARα, upregulates fatty acid oxidation-related genes, inhibits glycolysis, and improves myocardial energy metabolism.
- Reveals VA’s Regulation of the Pyruvate-Lactate Axis: VA suppresses LDHA and MCT4, promoting pyruvate oxidation and further improving cardiac energy metabolism disorders.
- Innovative Research Methods: Combining network pharmacology, molecular dynamics simulations, and SPR experiments to comprehensively elucidate the mechanisms of VA.
Additional Valuable Information
This study provides a theoretical foundation for the further development and clinical application of VA. Additionally, the research offers new insights into the design of PPARα agonists, holding significant scientific and practical value.