4-hydroxy-2-nonenal and Heart-Diseases

A major pathophysiological mechanism behind the development of diabetic heart diseases is oxidative stress mediated by toxic reactive aldehydes such as 4-hydroxynonenal (4HNE). Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that has been found to detoxify these deleterious aldehydes and thereby mitigate cardiac damage. Furthermore, its protective role in cellular signaling reverses aberrations caused by hyperglycemia, thereby protecting cardiac function. This chapter assesses the role of ALDH2 in diabetic heart diseases by examining preclinical studies where ALDH2 activity is perturbed in both decreased and increased directions. In doing so, issues in improving ALDH2 activity in select human populations are elucidated, and further research directions are discussed.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Diabetes Mellitus; Heart Diseases; Humans; Oxidative Stress

4-Hydroxy-2-nonenal (4-HNE), a reactive aldehyde, is generated from polyunsaturated fatty acids (PUFAs) in biological membranes. Reactive oxygen species (ROS) generated during oxidative stress react with PUFAs to form aldehydes like 4-HNE, which inactivates proteins and DNA by forming hybrid covalent chemical addition compounds called adducts. The ensuing chain reaction results in cellular dysfunction and tissue damage. It includes a wide spectrum of events ranging from electron transport chain dysfunction to apoptosis. In addition, 4-HNE directly depresses contractile function, enhances ROS formation, modulates cell signaling pathways, and can contribute to many cardiovascular diseases, including atherosclerosis, myocardial ischemia-reperfusion injury, heart failure, and cardiomyopathy. Therefore, targeting 4-HNE could help reverse these pathologies. This review will focus on 4-HNE generation, the role of 4-HNE in cardiovascular diseases, cellular targets (especially mitochondria), processes and mechanisms for 4-HNE-induced toxicity, regulation of 4-HNE metabolism, and finally strategies for developing potential therapies for cardiovascular disease by attenuating 4-HNEinduced toxicity.

Topics: Aldehydes; Animals; Apoptosis; Heart Diseases; Humans; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Heart diseases are the leading cause of death worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome.. The effects of LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) on cardiac tissue integrity and the plasma metabolome were assessed in adult male C57/BL6NRJ mice after eight weeks on the respective diet.. Both KDs resulted in increased amount of collagen fibers and cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the observed tissue remodeling is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway.. We conclude that regardless of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.

Topics: Animals; Diet, Ketogenic; Fatty Acids; Fibrosis; Heart Diseases; Male; Mice; Triglycerides

Coronary endothelial cell (EC) dysfunction including defective angiogenesis is reported in cardiac diseases. 4-Hydroxynonenal (4HNE) is a lipid peroxidation product, which is increased in cardiac diseases and implicated in cellular toxicity. Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that metabolizes 4HNE and reduces 4HNE-mediated cytotoxicity. Thus, we hypothesize that ALDH2 inhibition potentiates 4HNE-mediated decrease in coronary EC angiogenesis in vitro. To test our hypothesis, first, we treated the cultured mouse coronary EC (MCEC) lines with 4HNE (25, 50, and 75 μM) for 2 and 4 hours. Next, we pharmacologically inhibited ALDH2 by disulfiram (DSF) (2.5 μM) before challenging the cells with 4HNE. In this study, we found that 4HNE attenuated tube formation which indicates decreased angiogenesis. Next, we found that 4HNE has significantly downregulated the expressions of vascular endothelial growth factor receptor (VEGFR) 2 (P < .05 for mRNA and P = .005 for protein), Sirtuin 1 (SIRT 1) (P < 0.0005 for mRNA), and Ets-related gene (ERG) (P < 0.0001 for mRNA and P < 0.005 for protein) in MCECs compared with control. ALDH 2 inhibition by DSF potentiated 4HNE-induced decrease in angiogenesis (P < 0.05 vs 4HNE at 2 h and P < 0.0005 vs 4HNE at 4 h) by decreasing the expressions of VEGFR2 (P < 0.005 for both mRNA and protein), SIRT 1 (P < 0.05), and ERG (P < 0.005) relative to 4HNE alone. Thus, we conclude that ALDH2 acts as a proangiogenic signaling molecule by alleviating the antiangiogenic effects of 4HNE in MCECs.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Cell Line; Cells, Cultured; Diabetic Cardiomyopathies; Disulfiram; Down-Regulation; Endothelial Cells; Heart; Heart Diseases; Lipid Peroxidation; Mice; Myocardium; Neovascularization, Pathologic; Oncogene Proteins; RNA, Messenger; Sirtuin 1; Transcriptional Regulator ERG; Vascular Endothelial Growth Factor Receptor-2

Cardiovascular complications are major side effects of many anticancer drugs. Accumulated evidence indicates that oxidative stress in mitochondria plays an important role in cardiac injury, but how mitochondrial redox mechanisms are involved in cardiac dysfunction remains unclear. Here, we demonstrate that 4-hydroxy-2-nonenal (HNE) activates the translocation of the mitochondrial apoptosis inducing factor (AIFm2) and facilitates apoptosis in heart tissue of mice and humans. Doxorubicin treatments significantly enhance cardiac levels of HNE and AIFm2. HNE adduction of AIFm2 inactivates the NADH oxidoreductase activity of AIFm2 and facilitates its translocation from mitochondria. His 174 on AIFm2 is the critical target of HNE adduction that triggers this functional switch. HNE adduction and translocation of AIFm2 from mitochondria upon Doxorubicin treatment are attenuated by superoxide dismutase mimetics. These results identify a previously unrecognized role of HNE with important consequences for mitochondrial stress signaling, heart failure, and the side effects of cancer therapy.

Topics: Aldehydes; Animals; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Doxorubicin; Heart Diseases; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Heart; Oxidation-Reduction; Oxidative Stress; Oxidoreductases; Protein Transport; Signal Transduction

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension.

Topics: Adrenal Glands; Aldehydes; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Drug Therapy, Combination; Eplerenone; Heart Diseases; Hypertension; Lipid Peroxidation; Losartan; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Oxidative Stress; Rats, Sprague-Dawley; Renin-Angiotensin System; Signal Transduction; Spironolactone; Time Factors; Tyrosine

The pathogenesis of heart failure (HF) in diabetic individuals, called "diabetic cardiomyopathy", is only partially understood. Alterations in the cardiac autonomic nervous system due to oxidative stress have been implicated. The intrinsic cardiac nervous system (ICNS) is an important regulatory pathway of cardiac autonomic function, however, little is known about the alterations that occur in the ICNS in diabetes. We sought to characterize morphologic changes and the role of oxidative stress within the ICNS of diabetic hearts. Cultured ICNS neuronal cells from the hearts of 3- and 6-month old type 1 diabetic streptozotocin (STZ)-induced diabetic Sprague-Dawley rats and age-matched controls were examined. Confocal microscopy analysis for protein gene product 9.5 (PGP 9.5) and amino acid adducts of (E)-4-hydroxy-2-nonenal (4-HNE) using immunofluorescence was undertaken. Cell morphology was then analyzed in a blinded fashion for features of neuronal dystrophy and the presence of 4-HNE adducts.. At 3-months, diabetic ICNS neuronal cells exhibited 30% more neurite swellings per area (p = 0.01), and had a higher proportion with dystrophic appearance (88.1% vs. 50.5%; p = <0.0001), as compared to control neurons. At 6-months, diabetic ICNS neurons exhibited more features of dystrophy as compared to controls (74.3% vs. 62.2%; p = 0.0448), with 50% more neurite branching (p = 0.0015) and 50% less neurite outgrowth (p = <0.001). Analysis of 4-HNE adducts in ICNS neurons of 6-month diabetic rats demonstrated twice the amount of reactive oxygen species (ROS) as compared to controls (p = <0.001).. Neuronal dystrophy occurs in the ICNS neurons of STZ-induced diabetic rats, and accumulates temporally within the disease process. In addition, findings implicate an increase in ROS within the neuronal processes of ICNS neurons of diabetic rats suggesting an association between oxidative stress and the development of dystrophy in cardiac autonomic neurons.

Topics: Aldehydes; Animals; Autonomic Nervous System; Cells, Cultured; Cysteine Proteinase Inhibitors; Diabetes Mellitus, Experimental; Disease Models, Animal; Heart Diseases; Male; Myocardium; Neuroaxonal Dystrophies; Neurons; Neurotrophin 3; Rats; Rats, Sprague-Dawley; Ubiquitin Thiolesterase

Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H(2)) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H(2) gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H(2) gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H(2) gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H(2) gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H(2) gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.

Topics: Administration, Inhalation; Aldehydes; Analysis of Variance; Animals; Cholesterol, LDL; Cholesterol, VLDL; Disease Models, Animal; Dyslipidemias; Fibrosis; Free Radical Scavengers; Gases; Gene Expression Regulation; Heart Diseases; Heart Ventricles; Hemodynamics; Hydrogen; Hypoxia; Interleukin-6; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; RNA, Messenger; Superoxides; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Remodeling