Identification of antihypertensive peptides from doenjang-meju, Korean fermented soybean, and their effects on the renin-angiotensin system.

Although fermented soybean foods are recognized as sources of antihypertensive peptides, the microorganisms responsible for their production and the underlying mechanisms remain poorly understood. Here, defined starter cultures were used to directly link microbial fermentation with the generation of antihypertensive peptides in doenjang-meju. Among the tested starters, Bacillus velezensis produced the strongest angiotensin-converting enzyme (ACE)-inhibitory activity. Bioactivity-guided fractionation combined with LC-Q-TOF-MS identified two ACE-inhibitory peptides, SAGPV and GDSM. Both peptides significantly reduced blood pressure in high-fat diet-induced hypertensive mice, with efficacy comparable to captopril. Mechanistically, they decreased circulating ACE and angiotensin II levels, suppressed cardiac ACE expression, and restored the protective ACE2-MAS1 axis of the renin-angiotensin system. In addition, B. velezensis-fermented soybean attenuated hypertension more effectively than non-fermented soybean. These findings identify SAGPV and GDSM as antihypertensive peptides generated during B. velezensis fermentation and provide mechanistic evidence that targeted microbial fermentation can enhance the cardiovascular benefits of soybean foods.