Hyperglycemia-induced degradation of HIF-1α contributes to impaired response of cardiomyocytes to hypoxia

Ramalho, Ana Rita; Toscano, Adriana; Pereira, Paulo; Girão, Henrique; Gonçalves, Lino; Marques, Célio Gonçalo

doi:10.1016/j.repc.2016.09.018

Cited by 12 publications

(8 citation statements)

References 25 publications

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“…Indeed, in a low oxygen environment, HIF1α deficiency results in cell death 40 . The accumulation of MGO under hyperglycemia and the subsequent degradation of HIF1α are proposed as mechanisms underlying the detrimental effects of high glucose on various injuries, 41 such as hypoxic cardiomyocyte injuries 42 . MGO modifies HIF1α at its proline residues, leading to ubiquitination by the C-terminus of the HSC70-interacting protein (CHIP) and subsequent proteasome-dependent degradation 32 .…”

Section: Discussionmentioning

confidence: 99%

Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells

Aki

Funakoshi

Noritake

et al. 2020

Sci Rep

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extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells toshihiko Aki * , takeshi funakoshi, Kanako noritake, Kana Unuma & Koichi Uemura Pyroptosis, a type of inflammatory cell death, is dependent on the inflammatory caspase-mediated cleavage of gasdermin D (GSDMD), and the subsequent pore formation on plasma membranes through which interleukin (IL)-1β and IL-18 are released from cells. During proinflammatory activation, macrophages shift their metabolism from aerobic oxidative phosphorylation to anaerobic glycolysis. Hypoxia-inducible factor (HIF)1α is involved in the induction of IL-1β gene expression as well as the metabolic shift towards glycolysis. However, the relationships between pyroptosis and glycolysis, as well as between pyroptosis and HIF1α are poorly investigated. Here we show that lipopolysaccharide (LPS) stimulation of RAW264.7 murine macrophage cells results in pyroptosis when cells are cultured in high glucose medium. During pyroptosis, HIF1α activation occurs transiently followed by downregulation to sub-basal levels. HIF1α downregulation and pyroptosis are observed when cells are stimulated with LPS under high glucose conditions. We also found that intracellular levels of methylglyoxal (MGo), a side product of glycolysis, increase when cells are stimulated with LPS under high glucose conditions. The addition of glycolysis inhibitor and rapamycin suppresses HIF1α downregulation and pyroptosis. These results show that glycolysis plays a crucial role not only in pro-inflammatory activation, but also in pyroptosis in LPS-stimulated RAW264.7 macrophages. Immune cell activation, which often results in a lytic form of cell death called pyroptosis, is critical for host defense against pathogen invasions 1. Upon stimulation with lipopolysaccharides (LPS), which are components of the cell walls of gram-negative bacteria, macrophages are activated in a proinflammatory direction via the activation of inflammatory caspases. Caspase-1 is an inflammatory caspase involved in both the maturation and secretion of pro-inflammatory interleukin-1β (IL-1β) and IL-18 through plasma membrane pores 2-4. A gasdermin family protein, gasderminD (GSDMD), has been shown to be responsible for pore formation on the plasma membrane. GSDM family proteins comprise N-terminal and C-terminal domains as well as a linker connecting them. GSDMD cleavage in its linker by inflammatory caspases results in the release of the N-terminal domain (p30). GSDMD-p30 translocates to the plasma membrane where it assembles to form pores through which IL-1β and IL-18 are secreted from the cell 5-11. It has been reported that hyperglycemia is a risk factor for many illnesses including ischemic cardiovascular injuries 12 , renal diseases 13 , and sepsis 14. One of the detrimental effects of hyperglycemia on such diseases and injuries is its effect on inflammation. In response to stimulation by endotoxin and by bacterial as well as viral infection, a macrophage switches its metabolism from o...

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Section: Discussionmentioning

confidence: 99%

Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells

Aki

Funakoshi

Noritake

et al. 2020

Sci Rep

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“…The next level of diabetes-induced deregulation of HIF-1 signaling involves responses to hypoxia. Experiments with cells cultured in an environment combining hyperglycemia and hypoxia show increased degradation of the HIF-1α protein ( 70 , 71 ). Thus, diabetes not only causes hypoxia but also compromises HIF-1 signaling.…”

Section: Hif-1 Signaling In Diabetesmentioning

confidence: 99%

“…Diabetes is known to impair microvasculature ( 129 , 130 ); particularly, diabetic cardiomyopathy is associated with a loss of coronary capillaries that further increases tissue hypoxia ( 131 ). Since the combination of hypoxia and hyperglycemia increases degradation of the HIF-1α protein ( 70 , 71 ), the ability of the diabetic heart to respond to hypoxic conditions is compromised ( 101 ). Consistent with these data are experiments with altered HIF-1 signaling in mouse hearts.…”

Section: Diabetic Cardiomyopathymentioning

confidence: 99%

HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

2018

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The heart is able to metabolize any substrate, depending on its availability, to satisfy its energy requirements. Under normal physiological conditions, about 95% of ATP is produced by oxidative phosphorylation and the rest by glycolysis. Cardiac metabolism undergoes reprograming in response to a variety of physiological and pathophysiological conditions. Hypoxia-inducible factor 1 (HIF-1) mediates the metabolic adaptation to hypoxia and ischemia, including the transition from oxidative to glycolytic metabolism. During embryonic development, HIF-1 protects the embryo from intrauterine hypoxia, its deletion as well as its forced expression are embryonically lethal. A decrease in HIF-1 activity is crucial during perinatal remodeling when the heart switches from anaerobic to aerobic metabolism. In the adult heart, HIF-1 protects against hypoxia, although its deletion in cardiomyocytes affects heart function even under normoxic conditions. Diabetes impairs HIF-1 activation and thus, compromises HIF-1 mediated responses under oxygen-limited conditions. Compromised HIF-1 signaling may contribute to the teratogenicity of maternal diabetes and diabetic cardiomyopathy in adults. In this review, we discuss the function of HIF-1 in the heart throughout development into adulthood, as well as the deregulation of HIF-1 signaling in diabetes and its effects on the embryonic and adult heart.

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“…Compatible with this suggestion is the finding that knockdown of glyoxalase-1 in non-diabetic mice results in renal lesions indistinguishable from those of diabetic mice, while overexpression of glyoxalase-1 in diabetic mice prevents the development of nephropathy 18 . Other studies have shown that MGO impairs HIF-1α degradation and signaling 19,20 and activates AMPK mediated autophagic degradation of thioredoxin 1 21 , thus emphasizing its influence on redox homeostasis 22 . Despite the clear association between reactive carbonyl species and diabetic complications, their mode of action on endothelial cells is discussed ambiguously 23–27 .…”

Section: Introductionmentioning

confidence: 97%

Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells

Braun

Pastene

Breedijk

et al. 2019

Sci Rep

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Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.

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Hyperglycemia-induced degradation of HIF-1α contributes to impaired response of cardiomyocytes to hypoxia

Abstract: Taken together, the results obtained in this study suggest that MGO compromises the ability of cells to adapt to low oxygen tensions, by stimulating the degradation of HIF-1α, likely contributing to the development of diabetes-associated cardiac dysfunction.

Cited by 12 publications

References 25 publications

Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells

Extracellular glucose is crucially involved in the fate decision of LPS-stimulated RAW264.7 murine macrophage cells

HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells

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