Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase

Biswas, Sudipta; Gupta, Mohak; Chattopadhyay, Debasis; Mukhopadhyay, Chinmay K.

doi:10.1152/ajpheart.00718.2006

Cited by 55 publications

(61 citation statements)

References 39 publications

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“…Most studies attribute any deleterious effects of this association to overproduction of insulin by the β cells that eventually results in a classical induction of ER stress, UPR and eventual death of the β cell (Fonseca et al 2011). Although the concentrations used in this study are unlikely to be attained in the blood during hyperinsulinemia, they are in accord with those used in other studies regarding insulin effects on its target tissues (Biswas et al 2007, Guillen et al 2008, Du & Ding 2009. Furthermore, some studies report levels as high as 700-800 pM (Movassat et al 1997, Remington et al 2015.…”

Section: :3mentioning

confidence: 72%

“…The various nonpancreatic β cell lines so far studied are not classical insulin target cells; therefore, we performed additional experiments on a liver cell line (human liver carcinoma cells HepG2) that is considered a common insulin target and is used in numerous studies on IR signaling (Hah et al 1992, Fawcett et al 2001, Patel et al 2004, Biswas et al 2007). HepG2 cells were treated with insulin (100 nM) or a cytokine mixture alone or in combination for 24 h (as done for MIN6 cells) and measurements of caspase activity and cell reducing power were then made.…”

Section: Figurementioning

confidence: 99%

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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic β cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic β cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic β cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100 nM) for 24 h selectively increased the production of ROS in pancreatic β cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time-and dose-dependent decrease in cellular reducing power of pancreatic β cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos. The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H 2 O 2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic β cells.

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Section: :3mentioning

confidence: 72%

Section: Figurementioning

confidence: 99%

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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“…Insulin has been shown to be able to elevate ROS levels in hepatic cell line HepG2 and cardiac cell line H9c2 (41). However, it is not yet clear whether insulin can elevate ROS levels in primary cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase

Tan

Wang

et al. 2008

Journal of Biological Chemistry

173

147

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The forkhead transcription factor Foxo3a is able to inhibit cardiomyocyte hypertrophy. However, its underlying molecular mechanism remains to be fully understood. Our present study demonstrates that Foxo3a can regulate cardiomyocyte hypertrophy through transactivating catalase. Insulin was able to induce cardiomyocyte hypertrophy with an elevated level of reactive oxygen species (ROS). The antioxidant agents, including catalase and N-acetyl-L-cysteine, could inhibit cardiomyocyte hypertrophy induced by insulin, suggesting that ROS is necessary for insulin to induce hypertrophy. Strikingly, we observed that the levels of catalase were decreased in response to insulin treatment. The transcriptional activity of Foxo3a depends on its phosphorylation status with the nonphosphorylated but not phosphorylated form to be functional. Insulin treatment led to an increase in the phosphorylated levels of Foxo3a. To understand the relationship between Foxo3a and catalase in the hypertrophic pathway, we characterized that catalase was a transcriptional target of Foxo3a. Foxo3a bound to the promoter region of catalase and stimulated its activity. The inhibitory effect of Foxo3a on cardiomyocyte hypertrophy depended on its transcriptional regulation of catalase. Finally, we identified that myocardin was a downstream mediator of ROS in conveying the hypertrophic signal of insulin or insulin-like growth factor-1. Foxo3a could negatively regulate myocardin expression levels through up-regulating catalase and the consequent reduction of ROS levels. Taken together, our results reveal that Foxo3a can inhibit hypertrophy by transcriptionally targeting catalase.Myocardial hypertrophy is a compensatory response to increased hemodynamic load. It is often associated with poor clinical outcomes, including the development of cardiac systolic and diastolic dysfunction and ultimately heart failure (1-7). Hyperinsulinemia and cardiac hypertrophy are closely related. For example, insulin treatment can induce hypertrophy in cultured cardiomyocytes (8). In the animal model, chronic hyperinsulinemia leads to cardiac hypertrophy (9). In particular, hypertensive patients with left ventricular hypertrophy have a higher degree of hyperinsulinemia than hypertensive patients without left ventricular hypertrophy (10). Insulin-like growth factor-1 (IGF-1) 3 also is a potent hypertrophic stimulus both in vitro and in vivo (11). To prevent and/or reverse myocardial hypertrophy, it is necessary to identify and characterize the molecules that are involved in the hypertrophic cascades of insulin and IGF-1.The forkhead family of transcription factors are characterized by the presence of a conserved 100-amino acid DNA binding domain and participate in regulating diverse cellular functions such as apoptosis, differentiation, metabolism, proliferation, and survival (12). The Foxo (Forkhead bOX-containing protein, O sub-family) subgroup contains four members (Foxo1, Foxo3a, Foxo4, and Foxo6). It has been shown that Foxo1 and Foxo3a are expressed in the heart and ske...

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“…HIF-1 can also respond to a variety of non-hypoxic stimuli, including vasoactive peptides, cytokine and hormones [10][11][12]. These stimuli can initiate ROS production which then can activate the HIF-1 cascade.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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Cyanide produces degeneration of the nervous system in which different modes of cell death are activated in the vulnerable brain areas. In brain, the mechanism underlying the cell death is not clear. In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide-treated cells exhibited a time-and concentration-dependent apoptosis that was caspase-independent. Cyanide induced a rapid surge of intracellular reactive oxygen species (ROS) generation, followed by p38 mitogen-activated protein kinase (MAPK) activation and nuclear accumulation of hypoxia-inducible factor-1α (HIF-1α). Activation of p38 MAPK and HIF-1α accumulation were attenuated by N-acetyl-L-cysteine (antioxidant), catalase (hydrogen peroxide scavenger) or a selective p38 MAPK inhibitor (SB203580). Cyanide activated the hypoxia response element (HRE) promoter, which was also blocked by the antioxidants and SB203580. HRE activation was followed by increased BNIP3 gene transcription, as reflected by elevated BNIP3 mRNA and protein levels. BNIP3 upregulation was reduced by selective RNAi knockdown of HIF-1α. Overexpression of BNIP3 produced mitochondrial dysfunction (reduced membrane potential), caspase-independent apoptosis, and sensitization of the cells to cyanideinduced toxicity. Expression of a dominant negative mutant or RNAi knockdown of BNIP3 protected the cells from cyanide. It was concluded that cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondrial-mediated death.

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Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase

Cited by 55 publications

References 39 publications

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

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