Resveratrol Inhibits High Glucose-Induced H9c2 Cardiomyocyte Hypertrophy and Damage via RAGE-Dependent Inhibition of the NF-κB and TGF-β1/Smad3 Pathways

Abstract

Hyperglycaemia is associated with the development of cardiac vascular disease. Resveratrol (RES) is a naturally occurring polyphenolic compound that possesses many biological properties, including anti-inflammatory properties and antioxidation functions. Our study aimed to explore the RES’s protective roles on high glucose (HG)-induced H9c2 cells and the underlying mechanisms. Small-molecule inhibitors, western blotting (WB), as well as reverse-transcription PCR (RT-PCR) were employed to investigate the mechanisms underlying HG-induced damage in H9c2 cells. RES (40 μg/mL) treatment significantly alleviated HG-induced cardiac hypertrophy and cardiac dysfunction. RES abated the HG‐induced increase in the levels of extracellular matrix (ECM) components and inflammatory cytokines, reducing ECM accumulation and inflammatory responses. Additionally, RES administration prevented HG‐induced mitochondrion‐mediated cardiac apoptosis of myocardial cells. In terms of mechanisms, we demonstrated that RES ameliorated the HG‐induced overexpression of receptor for advanced glycation endproducts (RAGE) and downregulation of NF-κB signalling. Moreover, RES inhibited HG‐induced cardiac fibrosis by inhibiting transforming growth factor beta 1 (TGF‐β1)/Smad3‐mediated ECM synthesis in cultured H9c2 cardiomyocytes. Further studies revealed that the effects of RES against HG‐induced upregulation of NF-κB and TGF‐β1/Smad3 pathways were similar to those of FPS-ZM1, a RAGE inhibitor. Collectively, the results implied that RES might help alleviate HG‐induced cardiotoxicity via RAGE‐dependent downregulation of the NF-κB and TGF‐β/Smad3 pathways. This study provided evidence that RES can be developed as a promising cardioprotective drug.

Mechanism of action of non-coding RNAs and traditional Chinese medicine in myocardial fibrosis: Focus on the TGF-β/Smad signaling pathway

“…Resveratrol is a polyphenolic compound widely discovered in a variety of medicinal and edible plants, with anti-inflammatory, antioxidant, and anti-apoptotic pharmacological effects (Gambini et al, 2015). Zhu et al (2022) found that TGF-β1, a-SMA, ColI, and Smad3 were significantly expressed in HG-induced H9c2 cells and were downregulated by resveratrol treatment. Such findings reveal that resveratrol reduces the ECM deposition by restraining the activation of TGF-β1/Smad3 signaling pathway, thereby alleviating the HGinduced cardiac fibrosis.…”

Oxidative stress signaling in the pathogenesis of diabetic cardiomyopathy and the potential therapeutic role of antioxidant naringenin

“…In patients with diabetes, a large number of AGEs are formed and deposited in the myocardial microvascular endothelium and extracellular matrix by non-enzymatic glycation reaction under long-term continuous high glucose environment [ 63 ]. AGEs can change the structure of proteins, cross-link collagen molecules, and directly cause irreversible damage to myocardial microvascular endothelial cells [ 64 , 65 ]. In addition, AGEs bind to RAGE and activate AGE-RAGE signaling pathways, causing oxidative stress, inflammatory response, and protein kinase C activation, which further promote ROS production [ 66 , 67 ].…”