Chinese Rice Wine Lees-Derived Peptides Alleviate Hypertension by Dual Modulation of Vascular Remodeling and Mitochondrial Metabolism: Multilevel Evidence from Endothelial Cells and Hypertensive Rats

Rice wine lees-derived peptides (RWLP) exert antihypertensive effects via multitarget modulation of vascular and metabolic pathways. In EA.hy926 endothelial cells, peptides H5 (LIIPQH) and H6 (LIIPEH) enhanced NO production, reduced ET-1 and ROS levels, and upregulated eNOS expression. In spontaneously hypertensive rats, oral RWLP significantly reduced systolic and diastolic blood pressure, improved aortic morphology, and suppressed serum ACE and Ang II levels. Transcriptomic profiling revealed downregulation of RAS-related genes (<i>Ace</i>, <i>Cma1</i>), inhibition of PI3K-Akt and ECM remodeling pathways, and activation of mitochondrial energy metabolism, including oxidative phosphorylation and the TCA cycle. RWLP lowers blood pressure by improving endothelial function, attenuating vascular remodeling, and enhancing mitochondrial bioenergetics. These findings provide preclinical support for their potential as natural antihypertensive agents.