NAD Metabolism Research Articles

Effects of sirtuins on the riboflavin production in Ashbya gossypii.

This study focuses on sirtuins, which catalyze the reaction of NAD+-dependent protein deacetylase, for riboflavin production in A. gossypii. Nicotinamide, a known inhibitor of sirtuin, made the color of A. gossypii colonies appear a deeper yellow at 5mM. A. gossypii has 4 sirtuin genes (AgHST1, AgHST2, AgHST3, AgHST4) and these were disrupted to investigate the role of sirtuins in riboflavin production in A. gossypii. AgHST1∆, AgHST3∆, and AgHST4∆ strains were obtained, but AgHST2∆ was not. The AgHST1∆ and AgHST3∆ strains produced approximately 4.3- and 2.9-fold higher amounts of riboflavin than the WT strain. The AgHST3∆ strain showed a lower human sirtuin 6 (SIRT6)-like activity than the WT strain and only in the AgHST3∆ strain was a higher amount of acetylation of histone H3 K9 and K56 (H3K9ac and H3K56ac) observed compared to the WT strain. These results indicate that AgHst3 is SIRT6-like sirtuin in A. gossypii and the activity has an influence on the riboflavin production in A. gossypii. In the presence of 5mM hydroxyurea and 50µM camptothecin, which causes DNA damage, especially double-strand DNA breaks, the color of the WT strain colonies turned a deeper yellow. Additionally, hydroxyurea significantly led to the production of approximately 1.5 higher amounts of riboflavin and camptothecin also enhanced the riboflavin production even through the significant difference was not detected. Camptothecin tended to increase the amount of H3K56ac, but the amount of H3K56ac was not increased by hydroxyurea treatment. This study revealed that AgHst1 and AgHst3 are involved in the riboflavin production in A. gossypii through NAD metabolism and the acetylation of H3, respectively. This new finding is a step toward clarifying the role of sirtuins in riboflavin over-production by A. gossypii.Key points• Nicotinamide enhanced the riboflavin production in Ashbya gossypii.• Disruption of AgHST1 or AgHST3 gene also enhanced the riboflavin production in Ashbya gossypii.• Acetylation of H3K56 led to the enhancement of the riboflavin production in Ashbya gossypii.

Sirt1 promotes tissue regeneration in zebrafish through regulating the mitochondrial unfolded protein response

SummaryThe mitochondrial unfolded protein response (UPRmt) is an organellar stress signaling pathway that functions to detect and restore disruption of mitochondrial proteostasis. The UPRmt is involved in a wide range of physiological and disease conditions, including aging, stem cell maintenance, innate immunity, neurodegeneration, and cancer. Here we report that the UPRmt is integral to zebrafish fin regeneration. Taking advantage of a novel zebrafish UPRmt reporter, we observed that UPRmt activation occurs in regenerating fin tissue shortly after injury. Through chemical and genetic approaches, we discovered that the Sirt1-UPRmt pathway, best known for its role in promoting lifespan extension, is crucial for fin regeneration. The metabolism of NAD+ is an important contributor to Sirt1 activity in this context. We propose that Sirt1 activation induces mitochondrial biogenesis in injured fin tissue, which leads to UPRmt activation and promotes tissue regeneration.

A hydride transfer complex reprograms NAD metabolism and bypasses senescence

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled invitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.

P–175 Possible role of NAD+ metabolism in oocyte aging: insights from gene expression profiles in reproductive aged oocytes

Abstract Study question Does reproductive aging alter the expression of genes involved in NAD+ metabolism in the mammalian oocyte? Summary answer We found that aging alters the expression of thirty genes encoding for NAD+-producing and NAD+-consuming enzymes pathway in mouse MII oocytes. What is known already NAD, a multifunctional metabolite in living cells, is known to convert between its oxidized NAD+ and reduced NADH forms during nutrients breakdown; the intracellular NAD+/NADH redox state reflects cell ability in generating ATP energy. NAD+ is utilized by proteins that control gene expression, DNA repair, apoptosis, mitochondrial biogenesis (i.e. sirtuins). Raising NAD+ by inducing its biosynthesis leads to sirtuins activation, so directly linking the cellular redox state with signalling events. The NAD+ pool is set by a critical balance between NAD+ biosynthetic and NAD+ consuming pathways. NAD(P)H levels declined in aged oocytes and NAD+ precursors seem to counteract ovarian aging. Study design, size, duration Pools of 25 oocytes at MII stage were obtained from young (4–8 weeks) and reproductively aged (48–52 weeks) CD–1 mice and processed for the analysis of 41 genes participating in NAD+ biosynthetic and NAD+ consuming pathways NAD+ pathways. Each experiment was performed three times and data were subjected to bioinformatic analysis to unravel potential age-related effects on NAD metabolism. Participants/materials, setting, methods Mice were superovulated by intraperitoneal injection of PMSG followed by hCG 48h apart. MII oocytes were isolated by 0.3 mg/ml hyaluronidase. RNA was obtained from each sample by Arcturus PicoPure Kit, and reverse transcribed. Each cDNA was analysed in triplicate by employing a NAD Metabolism H41 Predesigned panel for use with SYBR® Green, containing 41 genes of the NAD pathway, 2 housekeeping genes and 6 control probes. Raw data were analysed by DataAssist software. Main results and the role of chance The comparison between aged and young oocytes were focused on genes showing an absolute fold change (FC) <0.7 or > 1.4, a present call in at least the 50% of experiments and a p-Value <0.05 (ANOVA). Excluding transcripts showing a concordant value < 80%, n.30 differentially expressed genes (DEGs) were found: n.26 transcripts down-expressed and n.4 genes up-regulated. Data obtained by Ingenuity Pathways Analysis (IPA) software (Ingenuity Systems) provide evidence that NAD+ biosynthesis in aged oocytes is severely compromised. Limitations, reasons for caution Our results on animal model must be taken with caution. Validation of NAD+ precursor or activators of NAD+ biosynthesis in vivo administration is required. Wider implications of the findings: Present results demonstrate that aging affect oocyte genes involved in the regulation of NAD+ availability and supports the hypothesis that modulation of NAD+ metabolism may be an “anti-aging” strategy. Overall, these data laid the foundation for a central role of NAD+ metabolism in the maintenance of oocyte competenc Trial registration number Not applicable

Enzymatic and Chemical Syntheses of Vacor Analogs of Nicotinamide Riboside, NMN and NAD.

It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide (VAD), a molecule that causes cell toxicity. Therefore, vacor may potentially be exploited to kill cancer cells. In this study, we have developed efficient enzymatic and chemical procedures to produce vacor analogs of NAD and nicotinamide riboside (NR). VAD was readily generated by a base-exchange reaction, replacing the nicotinamide moiety of NAD by vacor, catalyzed by Aplysia californica ADP ribosyl cyclase. Additionally, we present the chemical synthesis of the nucleoside version of vacor, vacor riboside (VR). Similar to the physiological NAD precursor, NR, VR was converted to the corresponding mononucleotide (VMN) by nicotinamide riboside kinases (NRKs). This conversion is quantitative and very efficient. Consequently, phosphorylation of VR by NRKs represents a valuable alternative to produce the vacor analog of NMN, compared to its generation from vacor by nicotinamide phosphoribosyltransferase (NamPT).

Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.

Interactions among mTORC, AMPK and SIRT: a computational model\xa0for cell energy\xa0balance and metabolism

BackgroundCells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals.MethodsTo understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+ -consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α.ResultsThe model simulates the interactions among key regulators such as AKT, mTORC1, AMPK, NAD+ , and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases.ConclusionsThis study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.AtFViZViCnpUcXrH8ZRFSNVideo

Chemical and Biochemical Reactivity of the Reduced Forms of Nicotinamide Riboside.

All life forms require nicotinamide adenine dinucleotide, NAD+, and its reduced form NADH. They are redox partners in hundreds of cellular enzymatic reactions. Changes in the intracellular levels of total NAD (NAD+ + NADH) and the (NAD+/NADH) ratio can cause cellular dysfunction. When not present in protein complexes, NADH and its phosphorylated form NADPH degrade through intricate mechanisms. Replenishment of a declining total NAD pool can be achieved with biosynthetic precursors that include one of the reduced forms of nicotinamide riboside (NR+), NRH. NRH, like NADH and NADPH, is prone to degradation via oxidation, hydration, and isomerization and, as such, is an excellent model compound to rationalize the nonenzymatic metabolism of NAD(P)H in a biological context. Here, we report on the stability of NRH and its propensity to isomerize and irreversibly degrade. We also report the preparation of two of its naturally occurring isomers, their chemical stability, their reactivity toward NRH-processing enzymes, and their cell-specific cytotoxicity. Furthermore, we identify a mechanism by which NRH degradation causes covalent peptide modifications, a process that could expose a novel type of NADH-protein modifications and correlate NADH accumulation with "protein aging." This work highlights the current limitations in detecting NADH's endogenous catabolites and in establishing the capacity for inducing cellular dysfunction.

Of mice and men: opposing effects of nicotinamide riboside on skeletal muscle physiology at rest and during exercise.

Of mice and men: opposing effects of nicotinamide riboside on skeletal muscle physiology at rest and during exercise.

NAD(P)H-triggered probe for dual-modal imaging during energy metabolism and novel strategy of enhanced photothermal therapy in tumor

The reduced coenzymes (NADH and NADPH) are an important product in energy metabolism and closely related to the occurrence and development of cancer. So it is necessary to use a powerful detection tool to visualize NAD(P)H in energy metabolism of tumor cells and find a new strategy to improve cancer treatment based on NAD(P)H. Herein, a novel multifunctional probe (Cy-N) is synthesized with good near-infrared fluorescence (NIRF) response to NAD(P)H and the photoacoustic (PA) and photothermal properties are successfully activated by NAD(P)H. The probe is successfully applied in visualizing NAD(P)H in energy metabolism of tumor cells and imaging NAD(P)H in bacteria. Moreover, the probe can be used to image NAD(P)H in energy metabolism of tumor-bearing mice by dual-modal imaging (NIRF and PA). More importantly, in terms of the role of NAD(P)H in energy metabolism, the photothermal therapy (PTT) is activated by NAD(P)H and a novel strategy of enhanced PTT is proposed by injecting glucose. As far as we know, this is the first probe to detect NAD(P)H in energy metabolism through dual-modal imaging, and also the first probe to activate PTT based on NAD(P)H, which will provide important information of the diagnosis and treatment of cancer.

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Our previous study demonstrated that deletion of NAMPT gene in projection neurons using Thy1-NAMPT−/− conditional knockout (cKO) mice causes neuronal degeneration, muscle atrophy, neuromuscular junction abnormalities, paralysis and eventually death. Here we conducted a combined metabolomic and transcriptional profiling study in vivo in an attempt to further investigate the mechanism of neuronal degeneration at metabolite and mRNA levels after NAMPT deletion. Here using steady-state metabolomics, we demonstrate that deletion of NAMPT causes a significant decrease of NAD+ metabolome and bioenergetics, a buildup of metabolic intermediates upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in glycolysis, and an increase of oxidative stress. RNA-seq shows that NAMPT deletion leads to the increase of mRNA levels of enzymes in NAD metabolism, in particular PARP family of NAD+ consumption enzymes, as well as glycolytic genes Glut1, Hk2 and PFBFK3 before GAPDH. GO, KEGG and GSEA analyses show the activations of apoptosis, inflammation and immune responsive pathways and the inhibition of neuronal/synaptic function in the cKO mice. The current study suggests that increased oxidative stress, apoptosis and neuroinflammation contribute to neurodegeneration and mouse death as a direct consequence of bioenergetic stress after NAMPT deletion.

Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury.

The kidney plays an important role in maintaining normal blood pH. Metabolic acidosis (MA) upregulates the pathway that mitochondria in the proximal tubule (PT) use to produce ammonia and bicarbonate from glutamine, and is associated with AKI. However, the extent to which MA causes AKI, and thus whether treating MA would be beneficial, is unclear. Gavage with ammonium chloride induced acute MA. Multiphoton imaging of mitochondria (NADH/membrane potential) and transport function (dextran/albumin uptake), oxygen consumption rate (OCR) measurements in isolated tubules, histologic analysis, and electron microscopy in fixed tissue, and urinary biomarkers (KIM-1/clara cell 16) assessed tubular cell structure and function in mouse kidney cortex. MA induces an acute change in NAD redox state (toward oxidation) in PT mitochondria, without changing the mitochondrial energization state. This change is associated with a switch toward complex I activity and decreased maximal OCR, and a major alteration in normal lipid metabolism, resulting in marked lipid accumulation in PTs and the formation of large multilamellar bodies. These changes, in turn, lead to acute tubular damage and a severe defect in solute uptake. Increasing blood pH with intravenous bicarbonate substantially improves tubular function, whereas preinjection with the NAD precursor nicotinamide (NAM) is highly protective. MA induces AKI via changes in PT NAD and lipid metabolism, which can be reversed or prevented by treatment strategies that are viable in humans. These findings might also help to explain why MA accelerates decline in function in CKD.

Maintenance of intestinal homeostasis by NAD metabolism

Maintenance of intestinal homeostasis by NAD metabolism

A Hydride Transfer Complex Reprograms NAD Metabolism Preventing Senescence

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a novel multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP +. This hydride transfer complex (HTC) is assembled by Malate Dehydrogenase-1, Malic Enzyme-1 and cytosolic Pyruvate Carboxylase. HTC enzymes are found in phase-separated bodies in the cytosol of cancer cells and can be assembled in vitro from purified proteins. They are repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors and cooperate with oncogenic RAS to transform primary cells. We provide evidence for a new multi-enzymatic complex that reprograms metabolism and prevents cellular senescence.

Metabolic Features of Mouse and Human Retinas: Rods versus Cones, Macula versus Periphery, Retina versus RPE.

SummaryPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle, and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine, and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

Mitochondria Control Cortical Cell Fate after Mitosis.

During brain development, the daughter cells of neural stem cells have to make a choice - either to become new stem cells or to differentiate into neurons. In a recent issue of Science, Iwata etal. (2020) show that these fate decisions can be determined after mitosis by mitochondrial remodeling.

Changes in NAD and Lipid Metabolism Drive Acidosis-Induced AKI

Changes in NAD and Lipid Metabolism Drive Acidosis-Induced AKI

Abstract 220: Emerging Roles of Altered NAD Metabolism in Diabetic Cardiomyopathy

Diabetes is linked to altered NAD metabolism whose causal roles in cardiac dysfunction are poorly understood. Synthesis, consumption and redox balance of NAD dictate NAD metabolism and its homeostasis, and we here explored their roles in diabetic cardiomyopathy. 16 week of Type 1 diabetes (T1D) to C57BL6N mice was associated with lowered cardiac NAD/NADH, mild systolic and more severe diastolic dysfunction. We next used mouse models with altered NAD metabolism to determine how NAD redox balance impacts diabetic cardiomyopathy. Using cardiac-specific Ndufs4-KO mice (cKO) as a model of latent decrease in cardiac NAD/NADH, we observed accelerated systolic and diastolic dysfunction (lowered fractional shortening, E’/A’ ratio, and increased e/E’ ratio) in male cKO mice stressed with chronic T1D. Cardiac hypertrophy (heart weight/tibia length), insulin depletion and hyperglycemia levels were similar in these mice. Serum metabolomic analyses (~240 metabolites) also showed unchanged aqueous and lipid metabolite levels, suggesting that the diabetic stresses on these hearts were similar. The accelerated dysfunction of T1D cKO hearts was also observed in another female cohort. Importantly, elevation of cardiac NAD levels to attenuate NAD redox imbalance mitigated the accelerated dysfunction of T1D cKO hearts. In another cohort, control and cKO mice were stressed by 16-week high fat diet feeding. Accelerated systolic and diastolic dysfunction, and increased hypertrophy were observed in T2D cKO mice with similar glycemic levels to control mice. The data suggested that NAD redox imbalance is a positive regulator of cardiac dysfunction induced by T1D or T2D. However, NAD-dependent pathogenic mechanism induced by T1D or T2D (e.g. hypertrophy) can be different, and is under further investigation. Tissue fibrosis and mRNA levels of pro-fibrotic genes, including Adamts proteinases, integrins, laminins, matrix metalloproteinases and collagens were unchanged in T1D cKO hearts. Therefore, the accelerated dysfunction of T1D cKO hearts is due to cardiomyocyte dysfunction. We examined how NAD metabolism, other than the redox balance, may alter cardiomyocyte function. Levels of metabolite and mRNA regulating NAD synthesis and consumption pathways were measured. Of 32 transcripts assayed, Nmrk2 levels were uniquely up-regulated in T1D cKO hearts, and lowered by elevation of cardiac NAD levels. NMRK product levels were concomitantly decreased in T1D cKO hearts. NAD-dependent global acetylation and inhibitory superoxide dismutase 2 acetylation were increased in T1D cKO hearts. Protein oxidation levels were concomitantly raised. Hyperacetylation in proteins like CaM kinase was associated with increased phosphorylation in troponin I, not in MyBPC or PLN in T1D cKO hearts. These data support the emerging, multifaceted roles of altered NAD metabolism in the progression of diabetic cardiomyopathy.

Immunometabolic Status of COVID-19 Cancer Patients.

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.

Peculiarities of Platelet Metabolism in Patients with Acute Coronary Syndrome with Anxiety-Depressive Disorders and Informativity of Enzymes in the Forecast of Development of Cardiovascular Complications.

Anxiety–depressive disorders (ADD) are a risk factor of cardiovascular mortality in patients with coronary artery disease (CAD). Acute coronary syndrome (ACS) is the main clinical manifestation of a progressing CAD. Metabolic processes disorder in platelets can be one of the causes of cardiovascular complications in patients with ACS and concomitant ADD. We studied platelets metabolism and prognostic informativity of NAD(P)-dependent dehydrogenases of platelets in ACS patients with ADD in terms of forecasting cardiovascular complications development over a year of observation. The levels of NAD- and NADP-dependent dehydrogenases of platelets were determined by means of a bioluminescent method during the first 24 h after admission to hospital and in dynamics in 10 days. Among 315 examined patients, ADD was found in 161 (51.1%). ACS patients with concomitant ADD had both cytoplasmic and mitochondrial processes impairment in platelets that consisted in a decrease of energy metabolism intensity, inhibition of anaerobic glycolysis reactions and lipid catabolism. After 12 months of follow-up, 41 (25.5%) cardiovascular complications were detected in the group of ACS patients with ADD and 20 (13.0%) in the group of ACS patients without ADD. According to the results of the analysis of the neural network based on NAD(P)-dependent dehydrogenases of platelets activity in ACS patients with ADD, indicators were obtained that are informative for predicting the development of recurrent cardiovascular complications.