Bailcalin Protects against Diabetic Cardiomyopathy through Keap1/Nrf2/AMPK-Mediated Antioxidative and Lipid-Lowering Effects

Abstract

Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.

Effect of Rosmarinic Acid and Sinapic Acid on Oxidative Stress Parameters in the Cardiac Tissue and Serum of Type 2 Diabetic Female Rats

“…In the cardiac tissue, similarly to the serum, the activity of antioxidative enzymes was elevated. These results are in line with some other reports [26,61], but there are also reports indicating a decrease in antioxidative enzymes activity in the heart of diabetic animals [24,33,58,62]. In the study conducted by Okutan et al regarding the effect of caffeic acid phenethyl ester on oxidative stress markers in the heart it was shown that similarly to our results, the activities of SOD and CAT were elevated in diabetic rats, while GPx activity was unchanged when compared to the non-diabetic animals.…”

“…Therefore, it can be concluded, that the model reflecting the changes observed in the type 2 diabetes in humans in the most adequate manner is a model in which a high-fat diet is combined with a single injection of a low dose of streptozotocin [52,53]. It should be noted that the majority of studies describing the effect of tested substances on parameters affected by both the type 1 and type 2 diabetes is based on the experiments conducted on male laboratory animals [17,[19][20][21][22][23][24][25][32][33][34][35]37,38,50,51,[54][55][56][57][58][59][60][61][62]. Following the suggestion of The National Institutes of Health (NIH) to use female animals in the laboratory studies [63] and reports about sex-dependent metabolic differences [64,65], our experiment was conducted on female rats.…”

Bakuchiol Alleviates Hyperglycemia-Induced Diabetic Cardiomyopathy by Reducing Myocardial Oxidative Stress via Activating the SIRT1/Nrf2 Signaling Pathway

“…As for Nrf2, another vital antioxidant sensor, it confers maintenance of cellular defense system by promoting the expressions of antioxidant molecules when its position shifts from the cytoplasm to the nucleus where it binds to AREs [ 55 , 56 ]. Many previous studies have already revealed the two redox-sensitive proteins closely implicated in the therapeutic effects on diabetic cardiomyopathy [ 21 , 46 , 57 , 58 ]. More importantly, SIRT1 is involved in the regulation and control of oxidative stress that are associated with diverse stimulus, which appears to be exerted by activating Nrf2, indicating that Nrf2 serves as an important downstream target of SIRT1 signaling [ 25 , 26 , 31 , 59 ].…”

Scutellarin protects against diabetic cardiomyopathy via inhibiting oxidative stress and inflammatory response in mice

“…One of the important pathological structural changes in diabetes is myocardial fibrosis (15,16). TGF-β1 signaling pathway is activated by continuous of hyperglycemia and then increased the level of fibrotic markers in hearts of diabetic mice, including α-SMA, Col I, and Col III (17).…”