Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both in vitro and in vivo, further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGFβ1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers α-SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.

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Melatonin functions as an endogenous protective molecule in multiple vascular diseases, whereas its effects on thoracic aortic aneurysm and dissection (TAAD) and underlying mechanisms have not been reported. In this study, TAAD mouse model was successfully induced by β‐aminopropionitrile fumarate (BAPN). We found that melatonin treatment remarkably prevented the deterioration of TAAD, evidenced by decreased incidence, ameliorated aneurysmal dilation and vascular stiffness, improved aortic morphology, and inhibited elastin degradation, macrophage infiltration, and matrix metalloproteinase expression. Moreover, melatonin blunted oxidative stress damage and vascular smooth muscle cell (VSMC) loss. Notably, BAPN induced a decrease in SIRT1 expression and activity of mouse aorta, whereas melatonin treatment reversed it. Further mechanistic study demonstrated that blocking SIRT1 signaling partially inhibited these beneficial effects of melatonin on TAAD. Additionally, the melatonin receptor was involved in this phenomenon. Our study is the first to report that melatonin exerts therapeutic effects against TAAD by reducing oxidative stress and VSMC loss via activation of SIRT1 signaling in a receptor‐dependent manner, thus suggesting a novel therapeutic strategy for TAAD.