Aldehydemetabolism in the cardiovascular system

Conklin, Daniel J.; Prough, Russell A.; Bhatanagar, Aruni

doi:10.1039/b612702a

Cited by 64 publications

(40 citation statements)

References 173 publications

(193 reference statements)

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“…Therefore, carbonylated proteins and lipids have to be degraded or metabolized to less reactive species via various detoxification pathways. Several enzymes including glutathione S-transferase, aldehyde dehydrogenase/cytochrome P450 and aldo-keto reductase can detoxify electrophilic aldehydes via conjugation with glutathione, oxidation or reduction [26]. Indeed, glutathione-S-transferase [27] and aldehyde dehydrogenase [28], [29] have been shown to play cardio-protective roles in IR injury and cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

et al. 2017

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Reactive oxygen and nitrogen species (ROS/RNS) play an important role in the regulation of cardiac function. Increase in ROS/RNS concentration results in lipid and protein oxidation and is often associated with onset and/or progression of many cardiovascular disorders. However, interplay between lipid and protein modifications has not been simultaneously studied in detail so far. Biomolecule carbonylation is one of the most common biomarkers of oxidative stress. Using a dynamic model of nitroxidative stress we demonstrated rapid changes in biomolecule carbonylation in rat cardiomyocytes. Levels of carbonylated species increased as early as 15 min upon treatment with the peroxynitrite donor, 3-morpholinosydnonimine (SIN-1), and decreased to values close to control after 16 h. Total (lipids+proteins) vs. protein-specific carbonylation showed different dynamics, with a significant increase in protein-bound carbonyls at later time points. Treatment with SIN-1 in combination with inhibitors of proteasomal and autophagy/lysosomal degradation pathways allowed confirmation of a significant role of the proteasome in the degradation of carbonylated proteins, whereas lipid carbonylation increased in the presence of autophagy/lysosomal inhibitors. Electrophilic aldehydes and ketones formed by lipid peroxidation were identified and relatively quantified using LC-MS/MS. Molecular identity of reactive species was used for data-driven analysis of their protein targets. Combination of different enrichment strategies with LC-MS/MS analysis allowed identification of more than 167 unique proteins with 332 sites modified by electrophilic lipid peroxidation products. Gene ontology analysis of modified proteins demonstrated enrichment of several functional categories including proteins involved in cytoskeleton, extracellular matrix, ion channels and their regulation. Using calcium mobilization assays, the effect of nitroxidative stress on the activity of several ion channels was further confirmed.

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Section: Introductionmentioning

confidence: 99%

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

et al. 2017

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“…However, tissue reactivity of aldehydes is regulated by processes involved in their metabolism and detoxification. 7 In most tissues, aldehydes are either reduced or oxidized to less reactive products. In addition, unsaturated aldehydes are conjugated to reduced glutathione (GSH) and are excreted as mercapturic acids in the urine.…”

Section: Introductionmentioning

confidence: 99%

Genetic Deficiency of Glutathione S -Transferase P Increases Myocardial Sensitivity to Ischemia–Reperfusion Injury

Conklin¹,

Guo²,

Jagatheesan³

et al. 2015

Circulation Research

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Rationale Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. Objective We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury. Methods and Results In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type (WT) mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism 4-hydroxy-trans-2-nonenal (HNE) or trans-2-hexanal; and, upon ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than WT hearts. GSTP-deficiency did not affect I/R-induced free radical generation, JNK activation or depletion of reduced glutathione. Acrolein-exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na+/Ca++ exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than WT myocytes to acrolein-induced protein crosslinking and cell death. Conclusions GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes such as acrolein.

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“…Aldehydes are unsaturated, highly reactive species that can form adducts with a number of biomacromolecules, including proteins, lipoproteins, nucleic acids, and many others (36,112,133,168,188). Very high levels of aldehyde adducts are detected in a number of complex disorders, such as cardiovascular disease and in disorders featuring neurodegeneration (Parkinson's and Alzheimer's diseases) (36,149,150), whereas lower concentrations of the free aldehydes have the capacity to alter intracellular signaling and gene regulation (27). What intracellular reactions and pathways will affect the level of SSA?…”

Section: E Mechanistic Considerations For Oxidant Stress In Ssadh Dementioning

confidence: 99%

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Kim

Pearl

Jensen

et al. 2011

Antioxidants & Redox Signaling

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADHdeficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation=reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691-718.

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Aldehydemetabolism in the cardiovascular system

Cited by 64 publications

References 173 publications

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

Genetic Deficiency of Glutathione S -Transferase P Increases Myocardial Sensitivity to Ischemia–Reperfusion Injury

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

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