Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

Abstract

Canagliflozin (Cana), an anti-diabetes drug belongs to sodium-glucose cotransporter 2 inhibitor, is gaining interest because of its extra cardiovascular benefits. Ferroptosis is a new mode of cell death, which can promote the occurrence of diabetic cardiomyopathy (DCM). Whether Cana can alleviate DCM by inhibiting ferroptosis is the focus of this study. Here, we induced DCM models in diabetic C57BL6 mice and treated with Cana. Meanwhile, in order to exclude its hypoglycemic effect, the high glucose model in H9C2 cells were established. In the in vivo study, we observed that Cana could effectively alleviate the damage of cardiac function in DCM mice, including the increasing of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), the alleviating of myocardial fiber breakage, inflammation, collagen fiber deposition and mitochondrial structural disorder. We evaluated reactive oxygen species (ROS) levels by DCFH-DA and BODIPY 581/591 C11, in vitro Cana reduced ROS and lipid ROS in H9C2 cells induced by high glucose. Meanwhile, JC-1 fluorochrome assay showed that the decreased mitochondrial membrane potential (MMP) was increased by Cana. Furthermore, the inhibitory effects of Cana on myocardial oxidative stress and ferroptosis were verified in vivo and in vitro by protein carbonyl (PCO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH). As a key inducer of ferroptosis, the deposition of total iron and Fe2+ can be inhibited by Cana both in vivo and in vitro. In addition, western blot results indicated that the expression of ferritin heavy-chain (FTN-H) was down-regulated, and cystine-glutamate antiporter (xCT) was up-regulated by Cana in DCM mice and cells, suggesting that Cana inhibit ferroptosis by balancing cardiac iron homeostasis and promoting the system Xc-/GSH/GPX4 axis in DCM. These findings underscore the fact that ferroptosis plays an important role in the development and progression of DCM and targeting ferroptosis may be a novel strategy for prevention and treatment. In conclusion, Cana may exert some of its cardiovascular benefits by attenuating ferroptosis.

Inflammation, dysregulated iron metabolism, and cardiovascular disease

“…Another example includes a study in which the effects of Canagliflozin (Cana) on ferroptosis in mice with DCM were examined. In this report, Cana reduced inflammatory cell infiltration into myocardial fibers and rescued the excess iron accumulation and glutathione depletion seen in ferroptosis (Du et al, 2022). As mentioned previously, ferroptosis is iron-induced cell death involving a loss of GPx4 activity and a subsequent increase in lipid reactive oxygen species, resulting in lipid peroxidation (Yang and Stockwell, 2016).…”

The Roles of Iron and Ferroptosis in Human Chronic Diseases

“…Due to the limited regenerative capacity of the myocardium in mammalian adult hearts, inhibition of cardiomyocyte death might be one of the important ways to alleviate DCM [103]. In our studies, we induced DCM models in diabetic C57BL6 mice and treated with canagliflozin and found that canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy [104]. Taken together, taking ferroptosis as the starting point may provide a new strategy for the prevention and control of DCM.…”

Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis

“…At the cellular level, the pathways of iron, amino acids and lipid metabolism are involved in the initiation and execution of ferroptosis (Du et al, 2022). As Figure 7 shown, iron, transported into cells by TfR1, is either stored in ferritin or exported by FPN1.…”

“…RNA was extracted and quantified according to the previous operation methods of our research group (Du et al, 2022). Total…”