Valine acts as an early biomarker and exacerbates pathological cardiac hypertrophy by impairing mitochondrial quality control

Objective: Pathological cardiac hypertrophy is an independent risk factor for heart failure (HF). Early identification and timely treatment are crucial for significantly delaying the progression of HF.

Methods: Targeted amino acid metabolomics and RNA Sequencing (RNA-seq) were combined to explore the underlying mechanism. In vitro, H9c2 cells were stimulated with angiotensin II (Ang II) or were incubated with extra valine after Ang II stimulation. The branched chain alpha-ketoate dehydrogenase kinase (Bckdk) inhibitor 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) and rapamycin were utilized to confirm the role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in this process.

Results: A significant accumulation of valine was detected within hypertrophic hearts from spontaneously hypertensive rats (SHR). When branched chain amino acid (BCAA) degradation was increased by BT2, the most pronounced decrease was observed in the valine level (Δ = 0.185 μmol/g, p < 0.001), and cardiac hypertrophy was ameliorated. The role of imbalanced mitochondrial quality control (MQC), including the suppression of Mitophagy and excessive mitochondrial fission, was revealed in myocardial hypertrophy. In vitro, high concentrations of valine exacerbated cardiomyocyte hypertrophy stimulated by Any II, resulting in the accumulation of impaired mitochondria and respiratory chain dysfunction. BT2, rapamycin, and mitochondrial division inhibitor 1 (Mdivi-1) all ameliorated MQC imbalance, mitochondrial damage and oxidative stress in hypertensive models with high valine concentration.

Conclusion: Valine exacerbated pathological cardiac hypertrophy by causing a MQC imbalance, probably as an early biomarker for cardiac hypertrophy under chronic hypertension.

Branched chain amino acids; Cardiac hypertrophy; Mitophagy; Oxidative stress; Valine.