Table of Contents
Preface…………………………………………………………………………………………………………………………………	2251
1. Lipid Peroxidation as a Free Radical Amplification Process…………………………………………………………………	2252
2. Structure, Properties and Generation of HNE…………………………………………………………………………………	2255
3. Major Reaction Mechanisms……………………………………………………………………………………………………	2257
3.1. Reactions of the C=C Double Bond……………………………………………………………………………………………	2257
3.1.1. Michael Additions…………………………………………………………………………………………………………	2257
3.1.2. Reduction…………………………………………………………………………………………………………………	2258
3.1.3. Epoxidation………………………………………………………………………………………………………………	2259
3.2. Reactions of the Carbonyl Group……………………………………………………………………………………………	2259
3.2.1. Acetal and Thio-Acetal Formation………………………………………………………………………………………	2259
3.2.2. Schiff-Base Formation……………………………………………………………………………………………………	2259
3.2.3. Oxidation…………………………………………………………………………………………………………………	2259
3.2.4. Reduction…………………………………………………………………………………………………………………	2260
3.3. Reactions of the Hydroxy Group………………………………………………………………………………………………	2262
4. Biophysical Effects………………………………………………………………………………………………………………	2262
5. Biochemical Targets of HNE……………………………………………………………………………………………………	2262
5.1. Reactions with Peptides and Proteins…………………………………………………………………………………………	2263
5.1.1. Substrates…………………………………………………………………………………………………………………	2265
5.1.1.1. Glutathione………………………………………………………………………………………………………………	2265
5.1.1.2. Carnosine………………………………………………………………………………………………………………	2267
5.1.1.3. Thioredoxin……………………………………………………………………………………………………………	2267
5.1.1.4. Cytochrome c……………………………………………………………………………………………………………	2268
5.1.2. Enzymes…………………………………………………………………………………………………………………	2268
5.1.2.1. Oxidoreductases…………………………………………………………………………………………………………	2269
5.1.2.1.1. Lactate Dehydrogenase………………………………………………………………………………………………	2269
5.1.2.1.2. Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH)…………………………………………………………	2269
5.1.2.2. Transferases……………………………………………………………………………………………………………	2270
5.1.2.2.1. Glutathione-S-Transferase (GST)……………………………………………………………………………………	2270
5.1.2.2.2. Liver Kinase B1 (LKB1)………………………………………………………………………………………………	2270
5.1.2.2.3. 5'-AMP-Activated Protein Kinase (AMPK)…………………………………………………………………………	2271
5.1.2.2.4. ZAK Kinase (Sterile Alpha Motif and Leucine Zipper Containing Kinase AZK)…………………………………	2271
5.1.2.2.5. Serine/Threonine-Protein Kinase AKT2 (Proteinkinase B2)………………………………………………………	2271
5.1.2.3. Hydrolases………………………………………………………………………………………………………………	2271
5.1.2.3.1. ATP Synthase…………………………………………………………………………………………………………	2271
5.1.2.3.2. Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN)……………………………………………	2272
5.1.2.3.3. Sirtuin 3 (SIRT3)……………………………………………………………………………………………………	2272
5.1.2.3.4. Cathepsins……………………………………………………………………………………………………………	2273
5.1.2.3.5. Neprilysin (NEP)……………………………………………………………………………………………………	2273
5.1.2.4. Lyases……………………………………………………………………………………………………………………	2273
5.1.2.4.1. Mitochondrial Aconitase (ACO2)……………………………………………………………………………………	2273
5.1.2.4.2. α-Enolase………………………………………………………………………………………………………………	2273
5.1.2.5. Isomerases………………………………………………………………………………………………………………	2274
5.1.2.5.1. Protein Disulfide Isomerase (PDI)……………………………………………………………………………………	2274
5.1.2.5.2. Peptidyl-Prolyl Cis/Trans-Isomerase A1 (Pin1)………………………………………………………………………	2274
5.1.2.6. Ligases: Glutamine Synthetase…………………………………………………………………………………………	2274
5.1.3. Carriers……………………………………………………………………………………………………………………	2274
5.1.3.1. Albumin…………………………………………………………………………………………………………………	2274
5.1.3.2. Hemoglobin and Myoglobin……………………………………………………………………………………………	2275
5.1.3.3. Liver and Adipocyte Fatty Acid-Binding Protein (FABP)……………………………………………………………	2275
5.1.3.4. Apolipoprotein B-100 (ApoB)…………………………………………………………………………………………	2275
5.1.3.5. β-Lactoglobulin…………………………………………………………………………………………………………	2276
5.1.4. Transporters and Channels………………………………………………………………………………………………	2276
5.1.4.1. Glutamate Transport Protein……………………………………………………………………………………………	2276
5.1.4.2. α-Synuclein (α-Syn)……………………………………………………………………………………………………	2276
5.1.4.3. Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA1a)……………………………………………………………	2277
5.1.4.4. Transient Receptor Potential Vanilloid 1 (TRPV1)……………………………………………………………………	2277
5.1.4.5. Dopamine Transporter…………………………………………………………………………………………………	2278
5.1.5. Receptors…………………………………………………………………………………………………………………	2278
5.1.5.1. Platelet-Derived Growth Factor Receptor-β (PDGFR-β)………………………………………………………………	2278
5.1.5.2. Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1)………………………………………………	2278
5.1.5.3. Toll-Like Receptor 4 (TLR4)……………………………………………………………………………………………	2278
5.1.6. Cytoskeletal Proteins………………………………………………………………………………………………………	2279
5.1.6.1. Tau Proteins……………………………………………………………………………………………………………	2279
5.1.6.2. Ankyrin…………………………………………………………………………………………………………………	2279
5.1.6.3. Spectrins…………………………………………………………………………………………………………………	2280
5.1.7. Chaperones: Heat Shock Proteins 70 and 90……………………………………………………………………………	2280
5.1.8. Uncoupling Proteins 2 and 3 (UCP2 and UCP3)…………………………………………………………………………	2282
5.1.9. Growth Factors: Platelet-Derived Growth Factor (PDGF)………………………………………………………………	2283
5.1.10. Peptide Hormones………………………………………………………………………………………………………	2283
5.1.10.1. Insulin…………………………………………………………………………………………………………………	2283
5.1.10.2. Angiotensin II…………………………………………………………………………………………………………	2283
5.1.11. Extracellular Matrix Proteins: Collagen…………………………………………………………………………………	2283
5.1.12. Histones: Histone-H2A…………………………………………………………………………………………………	2284
5.2. Reactions with Lipids…………………………………………………………………………………………………………	2284
5.3. Reactions with Cofactors and Vitamins………………………………………………………………………………………	2284
5.3.1. Vitamin C (Ascorbic Acid)………………………………………………………………………………………………	2284
5.3.2. Pyridoxamine……………………………………………………………………………………………………………	2285
5.3.3. Lipoic Acid………………………………………………………………………………………………………………	2285
5.4. Reactions with Nucleic Acids…………………………………………………………………………………………………	2285
6. Formation of HNE in Mammalian Cells and Tissues…………………………………………………………………………	2287
6.1. HNE Formation in Cellular and Organ Systems………………………………………………………………………………	2287
6.2. HNE in the Whole Healthy Organism…………………………………………………………………………………………	2289
6.3. Influence of Nutrition…………………………………………………………………………………………………………	2290
7. Metabolism of HNE………………………………………………………………………………………………………………	2291
7.1. HNE Metabolism in Mammalian Cells and Organs…………………………………………………………………………	2293
7.2. HNE Metabolism in Subcellular Organelles…………………………………………………………………………………	2294
7.3. HNE Metabolism in Whole Animals and Interorgan Relationships…………………………………………………………	2295
7.4. Primary HNE Intermediates—Enzymatic Reactions and Quantitative Results………………………………………………	2295
7.5. Secondary HNE Intermediates—Enzymatic Reactions and Quantitative Results……………………………………………	2301
7.6. HNE Metabolism as a Component of the Antioxidative Defense System……………………………………………………	2306
7.7. HNE Intermediates as Potential Biomarkers of LPO…………………………………………………………………………	2307
7.8. Further Medical Applications of HNE Metabolism…………………………………………………………………………	2307
8. Conclusions………………………………………………………………………………………………………………………	2309
Conflicts of Interest…………………………………………………………………………………………………………………	2309
Abbreviations………………………………………………………………………………………………………………………	2309
References……………………………………………………………………………………………………………………………	2313
Tables and Figures
Table 1. HNE concentrations in cells, tissues and organs……………………………………………………………………………	2289
Table 2. Maximal velocity of total HNE degradation in cells, subcellular organelles, and perfused organs…………………………………………………………………………………………………………………………………	2292
Table 3. Primary HNE metabolites in different cells and tissues after the addition of 100 μM HNE to the biological system…………………………………………………………………………………………………………………………………	2301
Figure 1. Idealized representation of the initiation and propagation reactions of lipid peroxidation	2253
Figure 2. Formation of lipid hydroperoxides and cyclic peroxides from arachidonic acid.…………………………………………	2254
Figure 3. Chemical structure of 4-hydroxy-2-trans-nonenal (HNE)…………………………………………………………………	2255
Figure 4. Overview of the reactions of 4-hydroxy-nonenal with different biomolecules……………………………………………	2257
Figure 5. HNE plasma concentration in dependence on age of the blood donor (5 to 90 years)……………………………………	2288
Figure 6. Degradation/metabolism of 4-HNE in rat hepatocytes……………………………………………………………………	2292
Figure 7. Identification of HNE and 4-hydroxynonenoic acid (HNA) by isocratic HPLC separation………………………………	2297
Figure 8. Mass spectrum of dihydroxynonene urethane (HPLC plus MS) with fluorimetric detection……………………………	2298
Figure 9. HNE metabolites.……………………………………………………………………………………………………………	2299
Figure 10. HPLC chromatogram of the isoindol derivative of the HNE-GSH conjugate (reaction product in presence of o-phthalaldehyde)………………………………………………………………………………………………………………………	2306