6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway

Abstract

Background. Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase risk of mortality. Objective. To characterize the therapeutic effect of 6-gingerol (6-G) on DCM and identify its potential mechanism. Methods. In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet and STZ, followed by low-dose (25 mg/kg) and high-dose (75 mg/kg) 6-G intervention. For an in vitro DCM model, H9c2 rat cardiomyoblast cells were stimulated with high glucose ( glucose = 33 mM) and palmitic acid (100 μM) and then treated with 6-G (100 μM). Histological and echocardiographic analyses were used to assess the effect of 6-G on cardiac structure and function in DCM. Western blotting, ELISA, and real-time qPCR were used to assess the expression of ferroptosis, inflammation, and the Nrf2/HO-1 pathway-related proteins and RNAs. Protein expression of collagen I and collagen III was assessed by immunohistochemistry, and kits were used to assay SOD, MDA, and iron levels. Results. The results showed that 6-G decreased cardiac injury in both mouse and cell models of DCM. The cardiomyocyte hypertrophy and interstitial fibrosis were attenuated by 6-G treatment in vivo and resulted in an improved heart function. 6-G inhibited the expression of ferroptosis-related protein FACL4 and the content of iron and enhanced the expression of anti-ferroptosis-related protein GPX4. In addition, 6-G also diminished the secretion of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. 6-G treatment activated the Nrf2/HO-1 pathway, enhanced antioxidative stress capacity proved by increased activity of SOD, and decreased MDA production. Compared with in vivo, 6-G treatment of H9c2 cells treated with high glucose and palmitic acid could produce a similar effect. Conclusion. These findings suggest that 6-G could protect against DCM by the mechanism of ferroptosis inhibition and inflammation reduction via enhancing the Nrf2/HO-1 pathway.

New Insights into the Role of Ferroptosis in Cardiovascular Diseases

“…Interestingly, Nrf2 activated by sulforaphane was shown to suppress cardiac cell ferroptosis in both AGE-treated ECTs and the hearts of diabetic cardiomyopathy mice by upregulating ferritin and SLC7A11 [ 150 ]. These protective effects on ferroptosis have been confirmed using other Nrf2 activators such as curcumin [ 163 ] and 6-gingerol [ 164 ] in animal models and in cardiomyocytes. Nevertheless, as emphasized above, it is known that Nrf2 increases HO-1 which degrades heme and makes available free iron that additionally favors lipid peroxidation [ 10 ].…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…its therapeutic potential against lung cancer (Tsai et al, 2020). In contrast, 6-Gingerol can inhibit ferroptosis in non-malignant conditions such as diabetic cardiomyopathy via enhancing NRF2/HO-1 activity, leading to antioxidative response and suppression of inflammation (Wu et al, 2022).…”

“…The modulation of key proteins associated with autophagy and ferroptosis both in vivo and in vitro underscores the intricate and multi‐faceted molecular mechanisms through which 6‐Gingerol exerts its therapeutic potential against lung cancer (Tsai et al, 2020). In contrast, 6‐Gingerol can inhibit ferroptosis in non‐malignant conditions such as diabetic cardiomyopathy via enhancing NRF2/HO‐1 activity, leading to antioxidative response and suppression of inflammation (Wu et al, 2022).…”

Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy

“…17 alleviates DCM through inhibiting ferroptosis by decreaseing the expression of FACL4 and the content of iron and enhancing the expression of Nrf2/GPX4 ( Wu X. et al, 2022 ). 18 , a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties, activates Nrf2/HO-1 signaling to relieve diabetic cardiomyopathy injury ( Ren et al, 2020 ; Wu et al, 2020 ; Wei et al, 2021 ; Wu S. et al, 2022 ). 18 alleviates DCM through inhibiting ferroptosis by activating Nrf2, leading to upregulating GPX4, highlighting a potentially new therapeutic route for investigation for the treatment DCM( Wei J. et al, 2022 ).…”