Cyclovirobuxine D protects against diabetic cardiomyopathy by activating Nrf2-mediated antioxidant responses

Abstract

Diabetic cardiomyopathy (DCM) is the principal cause of death in people with diabetes. However, there is currently no effective strategy to prevent the development of DCM. Although cyclovirobuxine D (CVB-D) has been widely used to treat multiple cardiovascular diseases, the possible beneficial effects of CVB-D on DCM remained unknown. The present aim was to explore the potential effects and underlying mechanisms of CVB-D on DCM. We explored the effects of CVB-D in DCM by using high fat high sucrose diet and streptozotocin-induced rat DCM model. Cardiac function and survival in rats with DCM were improved via the amelioration of oxidative damage after CVB-D treatment. Our data also demonstrated that pre-treatment with CVB-D exerted a remarkable cytoprotective effect against high glucose-or H 2 o 2-induced neonatal rat cardiomyocyte damage via the suppression of reactive oxygen species accumulation and restoration of mitochondrial membrane potential; this effect was associated with promotion of Nrf2 nuclear translocation and its downstream antioxidative stress signals (NQO-1, Prdx1). Overall, the present data has provided the first evidence that CVB-D has potential therapeutic in DCM, mainly by activation of the Nrf2 signalling pathway to suppress oxidative stress. Our findings also have positive implications on the novel promising clinical applications of CVB-D. Diabetic cardiomyopathy (DCM) is usually characterised by cardiac structure and functional disorders in individuals with diabetes independent of hypertension or ischemic coronary artery disease 1-3. Although it is the principal cause of death in patients with diabetes, no effective strategies currently exist to prevent the progression of DCM 4. The pathogenesis of DCM involves in many factors such as oxidative stress, chronic low-grade inflammation 5 , autophagy 6 , and pyroptosis 7 , etc. The accumulated evidences confirm that cardiomyocyte injuries induced by oxidative stress are the predominant contributors to the pathophysiological process of DCM 8. Reactive oxygen species (ROS) overproduction induced by hyperglycaemia, free fatty acids, and glycosylation end products results in myocardial structural damage and functional or metabolic disorders, which are considered to be the key pathological signal of DCM 9. Therefore, amelioration of oxidative stress may be a therapeutic strategy to prevent the progression of DCM. Nuclear factor (carotenoid-derived 2)-like 2 (Nrf2) is the major transcription factor in the cellular antioxidant response 10. The expression and activity of Nrf2 are regulated by cullin 3-based ubiquitin E3 ligases, such as Kelch-like ECH-related protein 1 (Keap1). Upon exposure to various stress conditions, Nrf2 is uncoupled from

Spiraeoside protects human cardiomyocytes against high glucose‐induced injury, oxidative stress, and apoptosis by activation of PI3K/Akt/Nrf2 pathway

“…Upon exposure to oxidative stress, Nrf2 is uncoupled from Keap1 and subsequently translocated into the nucleus, which is important for the activation of Nrf2. [ 32,33 ] The activation of Nrf2 regulates the transcriptional activation of important antioxidant enzymes such as HO‐1. [ 34 ] It has been proven that the activation of the PI3K/Akt pathway can indirectly regulate Nrf2.…”

Diabetic heart disease: A clinical update

“…Some of the newer antidiabetic drugs such as the GLP-1 RAs and the SGLT-2 inhibitors have exhibited direct protective effects on the myocardial tissue[ 120 ]. Therapeutic approaches including RNA-based therapy (a form of gene therapy), drugs targeting the mitochondrial oxidative stress, and metabolic modulator drugs including trimetazidine, ranolazine, perhexiline, alpha lipoic acid, resveratrol, luteolin, riboflavin, sodium ferulate, cyclovirobuxine, and epigallocatechin-3-gallate are currently being investigated for the prevention and treatment of DCM[ 121 - 123 ].…”

A review on herbal Nrf2 activators with preclinical evidence in cardiovascular diseases

“…Cardiomyocytes injuries due to increased production of ROS during hyperglycemic condition are principal cause of diabetic cardiomyopathy. Hence, mitigation of oxidative stress could be a therapeutic strategy to suppress the initiation and progression of diabetic cardiomyopathy (Jiang, Fu, et al, 2020; Jiang, Guo, et al, 2020). Recent years of evidence indicate that Nrf2/ARE signaling axis plays a crucial role in preventing hyperglycemia induced oxidative damage in the diabetic heart.…”