Role of Trimethylamine N-Oxide in Atherosclerosis: Inflammation, ER Stress and Beyond Trimetilamin N-Oksit'in Aterosklerozdaki Rolü: Enflamasyon, ER Stresi ve Ötesi

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RUMANLI Z., HACIŞEVKİ A.

Fabad Journal of Pharmaceutical Sciences, cilt.51, sa.2, ss.1113-1130, 2026 (Scopus)

Özet

Cardiovascular diseases (CVD) account for a significant proportion of deaths worldwide. The common pathological feature underlying these diseases is atherosclerosis, which is characterized as an inflammatory condition driven by endothelial cell activation and dysfunction in its early stages. While the effects of the microbiota and its metabolites on various systems are being actively investigated, their impact on the cardiovascular system has attracted particular attention. Some of the most compelling data on the role of the intestinal microbiota in cardiovascular diseases have emerged from the identification of novel metabolites and pathways associated with cardiovascular risk, as well as metabolic analyses of plasma samples. However, the role of the microbiota in these diseases is still not fully understood. Through the digestion of certain foods, such as animal proteins, gut microbiota generate metabolites that can contribute to the development of several major diseases. TMAO is one such metabolite and has recently received considerable attention, as it may act as both a risk factor and a link between the gut microbiota and various diseases, including cardiovascular conditions. Elevated circulating TMAO levels have also been associated with chronic kidney disease (CKD), and impaired renal clearance is thought to contribute to TMAO accumulation, thereby further increasing the risk of cardiovascular disease. Recent evidence also suggests that TMAO may promote cardiovascular pathology through the activation of endoplasmic reticulum (ER) stress signaling pathways. ER stress, which occurs when protein folding homeostasis in the endoplasmic reticulum is disrupted, has been associated with endothelial dysfunction, inflammation, and apoptosis, processes that contribute to the development and progression of atherosclerosis. This review aims to address atherosclerosis from the perspective of TMAO and to highlight studies examining the relationship between TMAO, CKD, ER stress, and atherosclerosis.