Pyridoxamine Reverts Methylglyoxal‐induced Impairment of Survival Pathways During Heart Ischemia

Almeida, Filipa; Santos-Silva, Daniela; Rodrigues, Tiago; Matafome, Paulo; Crisóstomo, Joana; Sena, Cristina M.; Gonçalves, Lino; Seiça, Raquel

doi:10.1111/1755-5922.12039

Cited by 23 publications

(26 citation statements)

References 32 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Using a Langendorff perfusion system, our group has shown decreased responsiveness to ischemia in hearts from MG‐supplemented rats . Such effects included the impairment of survival and apoptotic pathways and were prevented by pyridoxamine treatment . Recent data from our group shows that normal rats with MG dietary supplementation have impaired heart function evaluated by MRI, with decreased peak filling and ejection rates and stroke volume (unpublished data).…”

Section: Pathophysiological Relevance Of Methylglyoxal In Metabolic Dmentioning

confidence: 86%

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Matafome

Rodrigues

Sena

et al. 2016

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.

show abstract

Section: Pathophysiological Relevance Of Methylglyoxal In Metabolic Dmentioning

confidence: 86%

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Matafome

Rodrigues

Sena

et al. 2016

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

show abstract

“…15 In seeking links between glyoxal metabolism and necrosis, it is notable that both glycative stress and necrosis are implicated in the pathology of cardiac IR injury. [28][29][30] In addition, a mitochondrially-targeted MGO scavenging molecule was recently shown to protect the heart against IR injury. 31 To test the hypothesis that loss of ALKBH7 may protect against IR, perfused hearts from WT and Alkbh7 -/mice were subjected to IR injury (25 min.…”

Section: Loss Of Alkbh7 Protects the Heart From Ischemia-reperfusion mentioning

confidence: 99%

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy³

et al. 2020

Preprint

View full text Add to dashboard Cite

Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for necrotic cell death in response to DNA alkylating agents, but its physiologic role within tissues remains unclear.Herein, we show that ALKBH7 plays a key role in the regulation of dialdehyde metabolism, which impacts cardiac survival in response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we do not find evidence that ALKBH7 functions as a prolyl-hydroxylase. However, we do find that mice lacking ALKBH7 exhibit a significant increase in glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Consistent with increased dialdehyde production, metabolomics analysis reveals rewiring of metabolic pathways related to the toxic glycolytic by-product methylglyoxal (MGO), as well as accelerated glycolysis and elevated levels of MGO protein adducts, in mice lacking ALKBH7. Consistent with roles for both necrosis and glycative stress in cardiac IR injury, hearts from male but not female Alkbh7 -/mice are protected against IR, although somewhat unexpectedly this protection does not appear to involve modulation of the mitochondrial permeability transition pore. Highlighting the importance of MGO metabolism for the observed protection, removal of glucose as a metabolic substrate or pharmacologic inhibition of GLO-1 both abrogate cardioprotection in ALKBH7 deficient mice. Integrating these observations, we propose that ALKBH7 plays a role in the regulation of glyoxal metabolism, and that protection against necrosis and IR injury bought on by ALKBH7 deficiency originates from hormetic signaling in response to elevated MGO stress.

show abstract

“…The enzyme 6-phospho-2-kinase 2,6-bisphosphatase (Pfkfb3) generates fructose-2-6-bisphosphate; this enzyme is normally subject to continuous proteolytic degradation mediated by the ubiquitin/proteasome system, but if proteolysis of Pfkfb3 is inhibited, in neurones for example, glycolysis is stimulated and oxidative stress is increased, resulting in neurodegeneration [98,99]. Explanations of this phenomenon include decreased glutathione synthesis and increased MG formation due to the increased triose-phosphate generation [23,100]. Thus, the decline in the ubiquitin/proteasomal system, which characterises PD may also contribute to increased MG formation in the PD brain.…”

Section: Aging Proteostatic Dysfunction and Pdmentioning

confidence: 99%

On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine

Hipkiss¹

2017

Aging and disease

View full text Add to dashboard Cite

Recent research shows that energy metabolism can strongly influence proteostasis and thereby affect onset of aging and related disease such as Parkinson’s disease (PD). Changes in glycolytic and proteolytic activities (influenced by diet and development) are suggested to synergistically create a self-reinforcing deleterious cycle via enhanced formation of triose phosphates (dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate) and their decomposition product methylglyoxal (MG). It is proposed that triose phosphates and/or MG contribute to the development of PD and its attendant pathophysiological symptoms. MG can induce many of the macromolecular modifications (e.g. protein glycation) which characterise the aged-phenotype. MG can also react with dopamine to generate a salsolinol-like product, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinaline (ADTIQ), which accumulates in the Parkinson’s disease (PD) brain and whose effects on mitochondria, analogous to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), closely resemble changes associated with PD. MG can directly damage the intracellular proteolytic apparatus and modify proteins into non-degradable (cross-linked) forms. It is suggested that increased endogenous MG formation may result from either, or both, enhanced glycolytic activity and decreased proteolytic activity and contribute to the macromolecular changes associated with PD. Carnosine, a naturally-occurring dipeptide, may ameliorate MG-induced effects due, in part, to its carbonyl-scavenging activity. The possibility that ingestion of highly glycated proteins could also contribute to age-related brain dysfunction is briefly discussed.

show abstract

Pyridoxamine Reverts Methylglyoxal‐induced Impairment of Survival Pathways During Heart Ischemia

Cited by 23 publications

References 32 publications

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine

Contact Info

Product

Resources

About