Martelli Alma, Abate Federico, Roggia Michele, Benedetti Giada, Caradonna Eugenio, Calderone Vincenzo, Tenore Gian Carlo, Cosconati Sandro, Novellino Ettore, Stornaiuolo Mariano
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy.
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.
Antioxidants (Basel). 2025 Apr 25;14(5):517. doi: 10.3390/antiox14050517.
Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas.
氧化三甲胺（TMAO）是一种内源性渗透溶质，其产生始于人体肠道中的酶促反应，在肠道中微生物群从食物中释放出三甲胺（TMA），并在肝脏中结束，在肝脏中TMA被含黄素单加氧酶3（FMO3）氧化为TMAO。虽然生理浓度的TMAO有助于蛋白质保持其折叠状态，但这种代谢物的高水平是有害的，并会促进氧化应激、炎症和动脉粥样硬化。在人类中，循环TMAO水平升高使个体易患心血管疾病和慢性肾病，并增加死亡风险，尤其是在老年人中。TMAO如何发挥其负面影响仅得到了部分阐明。在高血压大鼠中，eNOS底物L-精氨酸和具有降低TMAO活性的营养保健品Taurisolo协同作用以降低动脉血压。在这里，我们研究了这种协同作用的分子机制，并证明Taurisolo的靶标TMAO作为内皮型一氧化氮合酶（eNOS）的直接抑制剂，并在其催化位点与L-精氨酸竞争，最终抑制小鼠主动脉中NO的产生和乙酰胆碱（Ach）诱导的舒张。
