N-Lac-Phe Ameliorates Myocardial Cell Death by Improving Mitochondrial Dysfunction, Ultimately Improving TAC-induced Heart Failure

Mitochondrial dysfunction and cardiomyocyte death drive pressure overload-induced heart failure (HF). N-lactylphenylalanine (N-Lac-Phe) plays an important role in the myocardial metabolic network after infarction. However, its role in chronic pressure overload heart failure remains unclear. This study examines N-Lac-Phe’s effects on cardiac function in transverse aortic constriction (TAC)-induced heart failure and mitochondrial function in Angiotensin II (Ang II)-injured H9c2 cardiomyoblasts. Human plasma Lac‑Phe levels were measured by liquid chromatography-mass spectrometry (LC-MS) and correlated with heart failure. In mice, echocardiography and other methods assessed the impact of Lac‑Phe on cardiac function, H9c2 cardiomyoblasts, and mitochondria. In vitro, H9c2 cells were treated with Ang II and Lac‑Phe, followed by analysis of apoptosis and mitochondrial dysfunction using immunoblotting and fluorescent staining. Plasma Lac‑Phe levels were negatively correlated with cardiac function. In TAC‑induced heart failure mice, Lac‑Phe administration improved cardiac function, attenuated myocardial injury including fibrosis, hypertrophy, apoptosis and ferroptosis, and alleviated the downregulation of MFN2. In Ang II‑injured H9c2 cardiomyoblasts, Lac‑Phe reduced apoptosis, restored mitochondrial function, and upregulated p‑AMPK, PGC‑1α and MFN2 expression. N-Lac-Phe correlates with cardiac function and improves TAC-induced heart failure by reducing apoptosis, ferroptosis, and mitochondrial damage. It may attenuate Ang II-induced apoptosis and mitochondrial dysfunction via the AMPK/PGC-1α/MFN2 axis.