Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

Sun, Pengbo; Wang, Yangyang; Ding, Yipei; Luo, Jingyi; Zhong, Jin; Xu, Ning; Zhang, Y; Xie, Weidong

doi:10.1016/j.isci.2021.102521

Cited by 23 publications

(27 citation statements)

References 56 publications

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“…In our previous experiments, we found that CAN exerts anti-inflammatory effects both in vivo and in vitro . CAN significantly attenuated lipotoxicity and inflammation in cardiomyocytes ( Sun et al, 2021 ). CAN significantly reduced IL-1β levels in the plasma and lung tissues of LPS-treated NIH mice and THP-1 cells stimulated by LPS ( Xu et al, 2018 ; Niu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the hypoglycemic effect, CAN is involved in a few activities that are independent of SGLT-2. Several studies and clinical trials have shown that CAN reduces the risk of cardiovascular events ( Neal et al, 2017 ; Kosiborod et al, 2018 ; Mahaffey et al, 2018 ; Sun et al, 2021 ). We previously found that CAN effectively alleviated the pathological changes in lung inflammation in LPS-treated NIH mice ( Xu et al, 2018 ; Niu et al, 2021 ) and reduced the level of IL-1β in lung tissue and plasma ( Niu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1

Niu

Zhang

et al. 2022

Front. Pharmacol.

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NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an important component of the innate immune system that mediates the secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. However, current studies have shown that the abnormal activation of the NLRP3 inflammasome is associated with inflammatory diseases such as atherosclerosis, diabetes, and pneumonia. In this study, we found that canagliflozin (CAN) transcriptionally inhibited NLRP3 inflammasome-related proteins by inhibiting the transduction of the nuclear factor κB signal. Autophagy is largely involved in the post-translational modifications of the NLRP3 inflammasome and is an important regulator of NLRP3 inflammasome assembly and activation. Bax-interacting factor 1 (Bif-1) plays an important role in autophagosome formation during early-stage autophagy. Our results are the first to indicate that CAN, a hypoglycemic drug, can inhibit the activation of NLRP3 inflammasome and inflammation by upregulating Bif-1 and autophagy in a non-hypoglycemic manner. This study provides new information regarding the treatment of patients with pneumonia, particularly those with concurrent diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1

Niu

Zhang

et al. 2022

Front. Pharmacol.

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“…Canagliflozin (CANA) is a kind of sodium-glucose cotransporter 2 (SGLT2) inhibitor which serves as a new hypoglycemic drug that decreases glucose reabsorption in the kidneys [10]. More and more studies indicate that CANA exhibit additional activities independent of the hypoglycemic effect [11,12]. Particularly, recent evidence has highlighted the inhibitory effects of several SGLT2 inhibitors on tumors.…”

Section: Introductionmentioning

confidence: 99%

Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway

Luo

Sun

Zhang

et al. 2021

IJMS

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The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer.

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“…Cana has also been shown to prevent carcinogenesis in mouse models of diabetes and nonalcoholic steatohepatitis-related hepatocarcinogenesis and pancreatic cancer [2][3][4]. Cana is renoprotective in mouse models of type 2 diabetes and cisplatin renotoxicity, and cardioprotective in mouse models of diabetes [5][6][7]. Additionally, Cana alleviates LPSinduced lung injury, has an anti-inflammatory effect in vivo and in vitro, and extends lifespan in male rats [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice

et al. 2022

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Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

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Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

Abstract: Canagliflozin ameliorated heart dysfunctions in HFD/ STZ-induced diabetic miceCanagliflozin inhibited lipotoxicity in palmitic acid-induced HL-1 cardiomyocytes mTOR-HIF-1a pathway mediated lipotoxicity in cardiomyocytes Canagliflozin bound to mTOR and inhibited mTOR-HIF-1a pathway

Cited by 23 publications

References 56 publications

Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1

Canagliflozin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Inhibiting NF-κB Signaling and Upregulating Bif-1

Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway

Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice

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