Low-Valine Diet Ameliorates Pathological Cardiac Hypertrophy by Inhibiting LONP1-Mediated Degradation of ATP5F1B in Male Rodents

The NHANES database was used to assess dietary valine intake and analyze its impact on cardiovascular events. In vivo, the effects of a high-valine diet on cardiac structure and function in male animals were evaluated. To explore the underlying mechanism, we constructed L-valine-conjugated agarose beads. Pull-down experiments combined with LC-MS/mass spectrometry (MS) were conducted to identify target proteins of valine. Furthermore, the effects of low-valine diets on pathological hypertensive cardiac hypertrophy and function were determined via echocardiography, histological evaluation, and molecular analysis. Additionally, we validated the role of ATP5F1B through AAV9-cTNT in the overexpression and knockdown of Atp5f1β in vivo. In vitro, siLonp1 was used to determine the role of LONP1 in ATP5F1B expression at the protein level. Results Meta-analysis combined with NHANES database findings revealed that among the three BCAAs, valine was significantly associated with cardiovascular disease risk, with cumulative dietary valine intake increasing the risk of cardiovascular events. In vivo, a high-valine diet exacerbated pathological cardiac hypertrophy and worsened cardiac dysfunction in hypertensive male animals, whereas reducing dietary valine content alleviated pathological hypertrophy and improved HF by decreasing cardiac tissue valine levels. The construction of valine-coated agarose beads followed by pull-down and mass spectrometry analysis revealed valine binding to ATP5F1B in hypertensive animal cardiac tissue. In vitro and in vivo experiments confirmed that dietary valine structural modification modulates myocardial cell mitochondrial structure, function, and oxidative stress levels by regulating ATP5F1B protein expression, thereby influencing hypertensive pathological myocardial hypertrophy and cardiac function. Furthermore, coimmunoprecipitation (Co-IP) coupled with LC-MS/MS revealed that valine binding to ATP5F1B induces a conformational change, thereby increasing LONP1-mediated degradation of the ATP5F1B protein. Prediction and validation revealed the MET443 site as the relevant binding site for ATP5F1B (-Val)-LONP1. Conclusion The dietary pattern of low-valine diets exerts potent cardioprotective effects by improving substance and energy metabolism in hypertensive cardiomyocytes and mitigating mitochondrial structural damage and oxidative stress injury, thereby offering novel therapeutic strategies for clinical adjunctive treatment of hypertensive individuals.