Dityrosine induces myocardial injury via Ang II-MAPK-Nrf2 pathway-mediated oxidative stress, mitochondrial dysfunction, and fibrosis in mice

Dityrosine (Dityr), a typical oxidized tyrosine product in processed foods, has been implicated in various non-communicable diseases, yet its impact on myocardial injury remains unclear. This study investigated the mechanisms of Dityr-induced cardiac dysfunction in mice. Male C57BL/6 mice were administered Dityr (320-32,000 μg/kg BW/day) for 15 weeks. Dityr exposure significantly elevated blood pressure, impaired cardiac function (reduced CK and CK-MB activity, increased Cr and BUN), and induced myocardial fibrosis (upregulated I-CTP, III-PNP, MMPs/TIMPs). Dityr upregulated angiotensin II (Ang II) and activated the p38 MAPK pathway, exacerbated oxidative stress (decreased GSH/GSSG, increased MDA), reduced the antioxidant capacity (reduced T-AOC, reduced SOD, CAT, and Gpx activity) and suppressed Nrf2/ARE-mediated antioxidant defenses (downregulated Ho-1, Gpx-1, Nqo1). Mitochondrial dysfunction was evident via ultrastructural damage, reduced ATP synthesis, mtDNA depletion, and membrane depolarization. Additionally, Dityr promoted cardiomyocyte apoptosis (increased Bax and caspase 3, decreased Bcl-2) and inflammatory responses (elevated TNF-α, IL-6, NF-κB). These findings demonstrate that Dityr induces myocardial injury through oxidative stress-mediated mitochondrial damage, fibrosis, and apoptosis. Our study further highlights that dysregulation of the Ang II-MAPK-Nrf2 pathway is a critical mechanism underlying Dityr-induced myocardial injury.