Discovery and mechanism of anti-hypertensive effect of a novel tripeptide (SYP) from medicinal fungus Ganoderma lingzhi

Ganoderma lingzhi is a new species of the prize medicinal mushroom Ganoderma (Agaricomycetes). Using angiotensin Ⅰ-converting enzyme (ACE) as a target, a tripeptide Ser-Tyr-Pro (SYP) was discovered with preponderant ACE inhibitory activity with an 50% inhibiting concentration (IC₅₀) value of 62.50 μg/mL attribute to the formed salt bridge and hydrogen bonds between SYP and ACE. SYP even maintained superior bioactivity after intestinal digestion, and exerted no cytotoxicity, but presented incomplete bioavailability in blood of spontaneous hypertensive rats (SHRs). Furthermore, it performed antihypertensive effect in vivo by inhibiting the influx of Ca²⁺ through activating endothelial NO synthase (eNOS)/NO/guanosine 3’,5’-cyclic monophosphate (cGMP) pathway, accompanied by attenuating angiotensin Ⅱ (Ang Ⅱ)/NADPH oxidase (NOX)/reactive oxygen species (ROS) pathway. This work not only discoverers a novel pharmacological ingredient from medicinal mushroom G. lingzhi for hypertension therapy, but also provides an insight into molecular mechanism of the ACE inhibitory peptide (ACEIP) on lowering blood pressure.