Lactate shuttle: from substance exchange to regulatory mechanism.

Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment metabolism. The exchange of lactate between the two cells via mono-carboxylate transporters (MCTs) is known as the lactate shuttle in cancer. Lactate shuttle is the core of cancer cell metabolic reprogramming between two cells such as aerobic cancer cells and hypoxic cancer cells, tumor cells and stromal cells, cancer cells and vascular endothelial cells. Cancer cells absorb lactate by mono-carboxylate transporter 1 (MCT1) and convert lactate to pyruvate via intracellular lactate dehydrogenase B (LDH-B) to maintain their growth and metabolism. Since lactate shuttle may play a critical role in energy metabolism of cancer cells, components related to lactate shuttle may be a crucial target for tumor antimetabolic therapy. In this review, we describe the lactate shuttle in terms of both substance exchange and regulatory mechanisms in cancer. Meanwhile, we summarize the difference of key proteins of lactate shuttle in common types of cancer.

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides.

Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases (LDHs) catalyze the interconversion of lactate to pyruvate and as such represent promising targets in cancer therapy. However, direct inhibition of the LDH active site is challenging from physicochemical and selectivity standpoints. However, LDHs are obligate tetramers. Thus, targeting the LDH tetrameric interface has emerged as an appealing strategy. In this work, we examine a dimeric construct of truncated human LDH to search for new druggable sites. We report the identification and characterization of a new cluster of interactions in the LDH tetrameric interface. Using nanoscale differential scanning fluorimetry, chemical denaturation, and mass photometry, we identified several residues (E62, D65, L71, and F72) essential for LDH tetrameric stability. Moreover, we report a family of peptide ligands based on this cluster of interactions. We next demonstrated these ligands to destabilize tetrameric LDHs through binding to this new tetrameric interface using nanoscale differential scanning fluorimetry, NMR water-ligand observed via gradient spectroscopy, and microscale thermophoresis. Altogether, this work provides new insights on the LDH tetrameric interface as well as valuable pharmacological tools for the development of LDH tetramer disruptors.

ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis.

BACKGROUND: Aerobic glycolysis is a unique tumor cell phenotype considered as one of the hallmarks of cancer. Aerobic glycolysis can accelerate tumor development by increasing glucose uptake and lactate production. In the present study, lactate dehydrogenase A (LDHA) is significantly increased within glioma tissue samples and cells, further confirming the oncogenic role of LDHA within glioma. METHODS: Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were applied for histopathological examination. The protein levels of LDHA, transporter isoform 1 (GLUT1), hexokinase 2 (HK2), phosphofructokinase (PFK) in target cells were detected by Immunoblotting. The predicted miR-9 binding to lncRNA Annexin A2 Pseudogene 2 (ANXA2P2) or the 3' untranslated region (UTR) of LDHA was verified using Luciferase reporter assay. Cell viability or apoptosis were examined by MTT assay or Flow cytometry. Intracellular glucose and Lactate levels were measured using glucose assay kit and lactate colorimetric assay kit. RESULTS: The expression of ANXA2P2 showed to be dramatically upregulated within glioma tissue samples and cells. Knocking down ANXA2P2 within glioma cells significantly inhibited cell proliferation and aerobic glycolysis, as manifested as decreased lactate and increased glucose in culture medium, and downregulated protein levels of glycolysis markers, GLUT1, HK2, PFK, as well as LDHA. miR-9 was predicted to target both lncRNA ANXA2P2 and LDHA. The overexpression of miR-9 suppressed the cell proliferation and aerobic glycolysis of glioma cells. Notably, miR-9 could directly bind to LDHA 3'UTR to inhibit LDHA expression and decrease the protein levels of LDHA. ANXA2P2 competitively targeted miR-9, therefore counteracting miR-9-mediated repression on LDHA. Within tissues, miR-9 exhibited a negative correlation with ANXA2P2 and LDHA, respectively, whereas ANXA2P2 and LDHA exhibited a positive correlation with each other. CONCLUSIONS: In conclusion, ANXA2P2/miR-9/LDHA axis modulates the aerobic glycolysis progression in glioma cells, therefore affecting glioma cell proliferation.

Critical thermal maxima of early life stages of three tropical fishes: Effects of rearing temperature and experimental heating rate.

Marine ectotherms are often sensitive to thermal stress, and certain life stages can be particularly vulnerable (e.g., larvae or spawners). In this study, we investigated the critical thermal maxima (CTmax) of larval and early juvenile life stages of three tropical marine fishes (Acanthochromis polyacanthus, Amphiprion melanopus, and Lates calcarifer). We tested for potential effects of developmental acclimation, life stage, and experimental heating rates, and we measured metabolic enzyme activities from aerobic (citrate synthase, CS) and anaerobic pathways (lactate dehydrogenase, LDH). A slightly elevated rearing temperature neither influenced CTmax nor CS activity, which otherwise could have indicated thermal acclimation. However, we found CTmax to either remain stable (Acanthrochromis polyacanthus) or increase with body mass during early ontogeny (Amphiprion melanopus and Lates calcarifer). In all three species, faster heating rates lead to higher CTmax. Acute temperature stress did not change CS or LDH activities, suggesting that overall aerobic and anaerobic metabolism remained stable. Lates calcarifer, a catadromous species that migrates from oceanic to riverine habitats upon metamorphosis, had higher CTmax than the two coral reef fish species. We highlight that, for obtaining conservative estimates of a fish species' upper thermal limits, several developmental stages and body mass ranges should be examined. Moreover, upper thermal limits should be assessed using standardized heating rates. This will not only benefit comparative approaches but also aid in assessing geographic (re-) distributions and climate change sensitivity of marine fishes.

The Biochemical and Clinical Perspectives of Lactate Dehydrogenase: An Enzyme of Active Metabolism.

BACKGROUND: Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These diverse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well. OBJECTIVE: The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases. METHODS: With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents. DISCUSSION: LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have diversified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases. CONCLUSION: LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.

Expression of lactate dehydrogenase is induced during hypoxia via HIF-1 in the mud crab Scylla paramamosain.

Lactate dehydrogenase (LDH) is a key enzyme involved in anaerobic metabolism in most organisms. In the present study, we determined the structure and function of LDH sequence in Scylla paramamosain (SpLDH) by gene cloning, expression and RNA interference techniques in order to explore the genetic characteristics of LDH and its relationship with HIF-1 during hypoxia. The full-length cDNA was 1453 bp with an open reading frame (ORF) of 996 bp, and encoded a polypeptide of 332 amino acids. Homology analysis showed that the SpLDH gene is highly similar to arthropods. The SpLDH transcript increased after hypoxia in all tested tissues. The silencing of HIF-1 blocked the increase in LDH mRNA and activity, which were induced by hypoxia in gill and muscle tissues. Our results indicated that SpLDH expression was regulated transcriptionally by HIF-1.

Exposure to Pb and Cd alters MCT4/CD147 expression and MCT4/CD147-dependent lactate transport in mice Sertoli cells cultured in vitro.

Sertoli cells (SCs) provide lactate as an energy substrate to develop germ cells during spermatogenesis. Lead (Pb) and cadmium (Cd) can induce SC toxicity. However, the mechanisms remain unclear. This study aimed to investigate the molecular mechanisms by which Pb and Cd alter lactate transport and production by SCs. Mouse SC line (15P-1 cells) were cultured in the absence and presence of lead acetate (PbAc, 1, 10, 20 and 30 µM) or cadmium chloride (CdCl2, 0.5, 5, 10 and 15 µM) for 24 h. The results showed that PbAc exposure significantly decreased lactate dehydrogenase (LDH) activity and mRNA level, intracellular and extracellular lactate, and MCT4 and CD147 protein levels but increased MCT4 and CD147 mRNA levels. However, PbAc did not alter the glucose uptake, glucose transporters 1 (GLUT1) and 3 (GLUT3) mRNA expression of SCs. Thus, PbAc mainly decreased lactate production by inhibiting LDH activity. In CdCl2-treated SCs, intracellular lactate content increased but extracellular lactate content decreased significantly, P < .05. The glucose uptake, LDH activity, and mRNA expression of GLUT1, GLUT3 and LDH, all significantly increased. But the mRNA and protein levels of MCT4 and CD147 significantly decreased. Moreover, the fluorescence intensity of co-localizations of the MCT4-CD147 complex dose-dependently decreased in the cell membrane. Thus, CdCl2 may reduce lactate export by suppressing MCT4 and CD147 expression. These results suggest that PbAc and CdCl2 disrupt lactate production and transport in mouse SCs by disturbing glycolysis or inhibiting MCT4-CD147 transporter expression and co-localizations.

Warburg effect, lactate dehydrogenase, and radio/chemo-therapy efficacy.

The anaerobic metabolism of glucose by cancer cells, even under well-oxygenated conditions, has been documented by Otto Warburg as early as 1927. Micro-environmental hypoxia and intracellular pathways activating the hypoxia-related gene response, shift cancer cell metabolism to anaerobic pathways. In the current review, we focus on a major enzyme involved in anaerobic transformation of pyruvate to lactate, namely lactate dehydrogenase 5 (LDH5). The value of LDH5 as a marker of prognosis of cancer patients, as a predictor of response to radiotherapy (RT) and chemotherapy and, finally, as a major target for cancer treatment and radio-sensitization is reported and discussed. Clinical, translational and experimental data supporting the uniqueness of the LDHA gene and its product LDH5 isoenzyme are summarized and future directions for a metabolic treatment of cancer are highlighted.

[Regulation mechanism of HIFs, PPARs and AMPK in hypoxic training-induced reduction of body weight].

Hypoxic exposure activates hypoxia inducible factors (HIFs) to up-regulate the expression of its target genes. These genes encode glucose metabolism related proteins, such as glucose transporters (GLUTs) and glycolysis related enzymes, including lactate dehydrogenase A (LDHA) and aldolase A (ALDA). Therefore, HIFs participate in oxygenolysis of glucose and play an important role in mediating hypoxia response and weight loss. Exercise training influences fatty acid metabolism, insulin sensitivity and body energy balance through activating peroxisome proliferator-activated receptors (PPARs), which plays an active role in losing weight. In addition, hypoxic exposure or exercise training can activate energy sensor 5'-AMP activated protein kinase (AMPK) in cells and promote oxidation of glucose and fatty acid and weight loss. It has been shown that hypoxic training exerts a better effects on controlling weight, compared with either hypoxic exposure or exercise training alone. This paper reviewed synergistic interactions among HIFs, PPARs and AMPK under hypoxic training and proposed possible mechanisms of hypoxic training-induced weight loss via AMPK-HIFs axis or AMPK-PPARs axis, thus providing theoretical guidance for application of hypoxic training in weight control.

MiR-323a-3p suppressed the glycolysis of osteosarcoma via targeting LDHA.

Accumulating evidence has demonstrated that there is critical involvement of miRNAs in the initiation and progression of cancers. Here, we showed that miR-323a-3p was significantly down-regulated in osteosarcoma (OS) tissues and cell lines. Overexpression of miR-323a-3p decreased the cell viability, colon formation and induced the apoptosis of OS cells. Using bioinformatics analysis, lactate dehydrogenase A (LDHA) was predicted as one of the down-steam targets of miR-323a-3p. Highly expressed miR-323a-3p significantly decreased both the mRNA and protein levels of LDHA. Inverse correlation between the expression of LDHA and miR-323a-3p was observed in OS tissues. Consistent with the function of LDHA in glycolysis of cancer cells, overexpression of miR-323a-3p attenuated the lactate production of OS cells. These results demonstrated that miR-323a-3p suppressed the growth of OS cells via targeting LDHA and inhibited the glycolysis of OS. This study provides insight into the molecular mechanism of miR-323a-3p in regulating OS.

Targeted gene knockdown validates the essential role of lactate dehydrogenase in Cryptosporidium parvum.

Cryptosporidium parvum is a zoonotic protozoan that can cause a life-threatening gastrointestinal syndrome in children and in immunocompromised adults. Currently, the only approved drug for treatment of Cryptosporidium infections in humans is nitazoxanide, but it is not effective in immunocompromised individuals or in children with malnutrition. This is compounded by the lack of genetic methods for studying and validating potential drug targets in the parasite. Therefore, in this study, we endeavoured to adapt the use of a phosphorodiamidate morpholino oligomer (morpholino) antisense approach to develop a targeted gene knockdown assay for use in C. parvum. We show that morpholinos, at non-toxic concentrations, are rapidly internalised by both C. parvum and host cells (HCT-8), and distribute diffusely throughout the cytosol. Using morpholinos to separately target C. parvum lactate dehydrogenase and putative arginine n-methyltransferase genes, within 36h of in vitro culture, we achieved over 10-fold down-regulation of the respective encoded proteins in C. parvum. Pursuant to this, we observed that knockdown of C. parvum lactate dehydrogenase produced a dramatic reduction in intracellular growth and development of C. parvum by 56h of culture. On the other hand, C. parvum putative arginine n-methyltransferase knockdown did not appear to have any effect on parasite growth, but nevertheless provided the proof-of-principle that the morpholino knockdown assay in C. parvum was consistent. Together, our findings present a gene regulation approach for interrogating gene function in C. parvum in vitro, and further provide genetic evidence for the essential role of C. parvum lactate dehydrogenase in fueling the growth and development of intracellular C. parvum.

Adaptations of protein structure and function to temperature: there is more than one way to 'skin a cat'.

Sensitivity to temperature helps determine the success of organisms in all habitats, and is caused by the susceptibility of biochemical processes, including enzyme function, to temperature change. A series of studies using two structurally and catalytically related enzymes, A4-lactate dehydrogenase (A4-LDH) and cytosolic malate dehydrogenase (cMDH) have been especially valuable in determining the functional attributes of enzymes most sensitive to temperature, and identifying amino acid substitutions that lead to changes in those attributes. The results of these efforts indicate that ligand binding affinity and catalytic rate are key targets during temperature adaptation: ligand affinity decreases during cold adaptation to allow more rapid catalysis. Structural changes causing these functional shifts often comprise only a single amino acid substitution in an enzyme subunit containing approximately 330 residues; they occur on the surface of the protein in or near regions of the enzyme that move during catalysis, but not in the active site; and they decrease stability in cold-adapted orthologs by altering intra-molecular hydrogen bonding patterns or interactions with the solvent. Despite these structure-function insights, we currently are unable to predict a priori how a particular substitution alters enzyme function in relation to temperature. A predictive ability of this nature might allow a proteome-wide survey of adaptation to temperature and reveal what fraction of the proteome may need to adapt to temperature changes of the order predicted by global warming models. Approaches employing algorithms that calculate changes in protein stability in response to a mutation have the potential to help predict temperature adaptation in enzymes; however, using examples of temperature-adaptive mutations in A4-LDH and cMDH, we find that the algorithms we tested currently lack the sensitivity to detect the small changes in flexibility that are central to enzyme adaptation to temperature.

Lactic dehydrogenase and cancer: an overview.

Despite the intense scientific efforts made, there are still many tumors that are difficult to treat and the percentage of patient survival in the long-term is still too low. Thus, new approaches to the treatment of cancer are needed. Cancer is a highly heterogeneous and complex disease, whose development requires a reorganization of cell metabolism. Most tumor cells downregulate mitochondrial oxidative phosphorylation and increase the rate of glucose consumption and lactate release, independently of oxygen availability (Warburg effect). This metabolic rewiring is largely believed to favour tumor growth and survival, although the underlying molecular mechanisms are not completely understood. Importantly, the correlation between the aerobic glycolysis and cancer is widely regarded as a useful biochemical basis for the development of novel anticancer strategies. Among the enzymes involved in glycolysis, lactate dehydrogenase (LDH) is emerging as a very attractive target for possible pharmacological approaches in cancer therapy. This review addresses the state of the art and the perspectives concerning LDH both as a useful diagnostic marker and a relevant molecular target in cancer therapy and management.

Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome, is a frequent complication of liver failure/disease. Increased concentrations of lactate are commonly observed in HE patients, in the systemic circulation, but also in the brain. Traditionally, increased cerebral lactate is considered a marker of energy failure/impairment however alterations in lactate homeostasis may also lead to a rise in brain lactate and result in neuronal dysfunction. The latter may involve the development of brain edema. This review will target the significance of increased cerebral lactate in the pathogenesis of HE.

Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy.

One of the principal biochemical characteristics of malignant cells compared to normal cells is a metabolic switch from oxidative phosphorylation to increased glycolysis, even under hypoxic conditions, and is termed the Warburg effect. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. It is elevated in many types of cancers and has been linked to tumor growth, maintenance, and invasion; therefore, its inhibition may restrict the energy supply in tumors and thereby reduce the metastatic and invasive potential of cancer cells. This enzyme is receiving a great deal of attention as a potential diagnostic marker or a predictive biomarker for many types of cancer and as a therapeutic target for new anticancer treatments. In this review, we summarize the role of LDHA in cancer, discuss its potential significance in clinical diagnosis and prognosis of cancer, and propose LDHA as a novel target for the inhibition of tumor growth and invasiveness.

Human lactate dehydrogenase A (LDHA) rescues mouse Ldhc-null sperm function.

By targeted disruption of the lactate dehydrogenase c (Ldhc) gene, we demonstrated that spermatozoa require Ldhc for capacitation, motility, and fertilizing capacity. Ldhc expression is restricted to the developing germ cells that, however, are apparently not compromised by the lack of the LDHC isozyme. Because LDHC is abundant in spermatozoa that utilize aerobic glycolysis for energy requirements, its main function was presumed to be the interconversion of pyruvate to lactate with the concomitant oxidation/reduction of NADH to NAD(+). We found that sperm without LDHC were still able to convert lactate to pyruvate as mediated by LDHA that is tightly bound to the fibrous sheath. It was assumed that the level of glycolysis was insufficient to power motility and the subsequent fertilizing capacity of the mutated sperm. To investigate whether LDHC possesses certain unique characteristics essential for fertility, human LDHA was introduced as a transgene to Ldhc-null mice. We report here that the exogenous LDHA rescued the phenotype of the Ldhc-null males. Sperm from the LDHA transgenic males with the Ldhc deletion (LDHA(+)/Ldhc(-/-)) are motile, capable of protein tyrosine phosphorylation, and able to fertilize, thus restoring these properties to LDHC-null sperm. However, the lactate and ATP levels in the rescued sperm did not differ significantly from sperm lacking LDHC. We suggest that it is the localization of the transgene to the sperm cytosol that is mainly responsible for restoration of sperm function and fertility.

A comparison of muscle damage, soreness and performance following a simulated contact and non-contact team sport activity circuit.

The aim was to compare the effect of a simulated team sport activity circuit (reflective of the activity demands of Australian football) either with or without body 'contact' on muscle soreness, damage, and performance when the circuit was repeated 48 h later. Eleven male, team-sport athletes completed a 'non-contact' (NCON) and a 'contact' (CON) version of the team sport activity circuit in a crossover design with at least 1 week between trials. The effect of CON and NCON on repeated 15m sprint and vertical jump performance was assessed by completing the same version of the circuit 48 h after the initial trial. The effect on perceived soreness and blood markers of muscle damage and inflammation was also determined. Subsequent performance was affected to a greater extent by CON, with both best and mean sprint times significantly slower 48h following CON (p<0.05), while performance was maintained after NCON. Best and mean vertical jump performance was significantly impaired following CON (p<0.05), while only best vertical jump was affected by NCON (p<0.05). Perceived soreness and pressure sensitivity were elevated following both NCON and CON (p<0.001); however, the increase in soreness was greater with CON (p=0.012). Both CON and NCON resulted in elevated serum creatine kinase, myoglobin and lactate dehydrogenase, while c-reactive protein increased following CON but not NCON. In conclusion, Greater perceived soreness and decrements in performance of the simulated team sport activity circuit when repeated 48 h later were observed following CON.

The changes of the specific physiological parameters in response to 12-week individualized training of young soccer players.

The aim of this study was to analyze the influence of individualized training (IT) as a function of motor type and effort status on changes of in specific physiological parameters among young soccer competitors. Blood pH and lactate concentrations, and lactate dehydrogenase (LDH), and creatine kinase (CK) activities were measured at the beginning of a preparation period, a match season, and a recuperation period of a 6-month macrocycle. The differences among specific physiological parameters as a function of the preparation phase for a defined motor type were analyzed by means of a 1-way generalized linear model (GLM) for repeated measurements. The differences in physiological parameters among defined motor types for a defined preparation phase were analyzed by means of the GLM for independent data. The differences in specific parameters before and after short time effort were analyzed by means of a t-test for matched pairs. Applied experimental and analytical approaches have revealed that IT administered to specific motor types differentiates players with respect to the pH, lactate concentration, and LDH activity. Obtained results indicate also that the dynamics of these parameters reflects the player's fitness level. Analysis of CK activity as a function of a preparation phase may serve as a prognostic tool for both overtraining and physical exhaustion.

Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation.

Pulmonary microvascular endothelial cells possess both highly proliferative and angiogenic capacities, yet it is unclear how these cells sustain the metabolic requirements essential for such growth. Rapidly proliferating cells rely on aerobic glycolysis to sustain growth, which is characterized by glucose consumption, glucose fermentation to lactate, and lactic acidosis, all in the presence of sufficient oxygen concentrations. Lactate dehydrogenase A converts pyruvate to lactate necessary to sustain rapid flux through glycolysis. We therefore tested the hypothesis that pulmonary microvascular endothelial cells express lactate dehydrogenase A necessary to utilize aerobic glycolysis and support their growth. Pulmonary microvascular endothelial cell (PMVEC) growth curves were conducted over a 7-day period. PMVECs consumed glucose, converted glucose into lactate, and acidified the media. Restricting extracellular glucose abolished the lactic acidosis and reduced PMVEC growth, as did replacing glucose with galactose. In contrast, slow-growing pulmonary artery endothelial cells (PAECs) minimally consumed glucose and did not develop a lactic acidosis throughout the growth curve. Oxygen consumption was twofold higher in PAECs than in PMVECs, yet total cellular ATP concentrations were twofold higher in PMVECs. Glucose transporter 1, hexokinase-2, and lactate dehydrogenase A were all upregulated in PMVECs compared with their macrovascular counterparts. Inhibiting lactate dehydrogenase A activity and expression prevented lactic acidosis and reduced PMVEC growth. Thus PMVECs utilize aerobic glycolysis to sustain their rapid growth rates, which is dependent on lactate dehydrogenase A.

Epidermal growth factor protects the heart against low-flow ischemia-induced injury

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The role of ErbB4 and ErbB2 in the heart of adult mammals is well established. The heart also expresses ErbB1 (the epidermal growth factor (EGF) receptor), but this receptor has received less attention. We studied the effect of EGF on the response of isolated mouse heart to low-flow ischemia and reperfusion. Reducing perfusate flow to 10% for 30 min resulted in an increase inanaerobic metabolism and the leakage of lactate dehydrogenase during reperfusion. In addition, left ventricle +dP/dt and developed pressure were depressed (20–25%) during reperfusion. The addition of EGF 5 min before and throughout the ischemic period prevented the increase in anaerobic metabolism and the leakage of intracellular lactate dehydrogenase during reperfusion. EGF improved both +dP/dt and developed pressure during ischemia and prevented the decrease in dP/dt during reperfusion. To determine whether the effect of EGF on cell integrity depends on its effect on contractility, we studied nonbeating isolated myocytes. In these cells, anoxia and reoxygenationreduced cell viability by nearly 25%. EGF prevented such a decrease. Our results indicate that, like ErbB4 and ErbB2, ErbB1 also has an important role in the heart of adult animals (AU)