Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Dai, Chongshan; Li, Qinfeng; May, Herman I.; Li, Chao; Zhang, Guangyu; Sharma, Gaurav; Sherry, A. Dean; Malloy, Craig R.; Khemtong, Chalermchai; Zhang, Yuannyu; Deng, Yingfeng; Gillette, Thomas G.; Xu, Jian; Scadden, David T.; Wang, Zhao V.

doi:10.1016/j.celrep.2020.108087

Cited by 53 publications

(43 citation statements)

References 53 publications

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“…These results revealed that the hemodynamic changes precede the LVH-related morphological changes in the current study. 25 Generally, the chronological order of the IVPG is explained as elevated basal IVPG with maintained midto-apical IVPG in the early stages of LVH, which implies elevated LA pressure and maintained active relaxation. We speculate that the basal and mid-toapical IVPG may decrease in the late stage of LVH, since the heart may lose its ability to maintain the high LA pressure and active relaxation and compensated by the fibrosis and scarred myocardium in the late stage of LVH.…”

Section: Discussionmentioning

confidence: 99%

Intraventricular pressure gradients change during the development of left ventricular hypertrophy: Effect of salvianolic acid B and beta-blocker

Mandour

Yoshida

et al. 2021

Ultrasound

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Introduction Intraventricular pressure gradient is regarded as a non-invasive indicator of diastolic function. Salvianolic acid B (Sal-B), a traditional Asian medicine, revealed its usefulness in myocardial infarction models; however, the hemodynamic effect of salvianolic acid B is still unknown. The present study aimed to investigate the intraventricular pressure gradient changes during the development of left ventricular hypertrophy with or without salvianolic acid B and a beta-blocker. Methods In total, 48 rats were divided into four groups; Sham, Non-treatment, salvianolic acid B, and Carvedilol. Aortic coarctation-induced left ventricular hypertrophy was done in three groups and the treatment was started from the third to the sixth week. Blood pressure, conventional echocardiography, and color M-mode echocardiography for measurement of intraventricular pressure gradient were carried out for six consecutive weeks. Results At 4.5 weeks, the LV mass was elevated in the coarctation groups but the blood pressure was significantly lower in salvianolic acid B and Carvedilol groups ( P < 0.05). In the Non-treatment group, the total intraventricular pressure gradient was increased at 4.5 and 6 weeks (2.60 and 2.65, respectively). Meanwhile, the basal intraventricular pressure gradient was elevated at 3 and 6 weeks (1.67 and 1.75) compared with the Sham group. Salvianolic acid B and Carvedilol significantly reduced the basal intraventricular pressure gradient at six weeks compared with the Non-treatment group (1.52 and 1.51 vs 1.75, respectively). Conclusions Salvianolic acid B and Carvedilol promote cardiac function by decreasing the elevated basal intraventricular pressure gradient. The current preclinical results revealed the efficacy of salvianolic acid B as a potential therapy for left ventricular hypertrophy because of the non-blood pressure lowering effect.

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Section: Discussionmentioning

confidence: 99%

Intraventricular pressure gradients change during the development of left ventricular hypertrophy: Effect of salvianolic acid B and beta-blocker

Mandour

Yoshida

et al. 2021

Ultrasound

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“…A critical step in the pathway is the involvement of lactate dehydrogenase (LDH), an enzyme that catalyses the reversible conversion of lactate to pyruvate [ 51 , 52 ]. Specifically, the LDHA1 isoenzyme shows a greater affinity for pyruvate and mediates the preferential conversion of pyruvate to lactate [ 53 , 54 ]. We initially determined the expression of lactate dehydrogenase (LDHA1) as an indicator of greater reliance on aerobic glycolysis in these cells.…”

Section: Resultsmentioning

confidence: 99%

An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T)

Yeo

Subramanian

Chong

et al. 2021

Molecular Metabolism

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Background ATM, the protein defective in the human genetic disorder, ataxia-telangiectasia (A-T) plays a central role in response to DNA double-strand breaks (DSBs) and in protecting the cell against oxidative stress. We showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2 + transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress. Methods We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2- deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 h using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca 2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS assay to determine altered levels of TCA intermediates A-T cells compared to healthy control cells. Results We demonstrate that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases the resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate, and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate. Conclusions We conclude that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has immense potential as a novel therapeutic agent for patients with A-T.

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“…This could suggest a significant conversion of pyruvate to lactate in this group of animals. It has been previously reported that cardiomyocytes undergo hypertrophic changes due to elevated LDH activity, which stimulates NDRG3 expression by increasing lactate generation, followed by cell growth in animals with metabolic disorders [ 52 ]. These compensatory mechanisms are activated in order to prevent heart failure [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously reported that cardiomyocytes undergo hypertrophic changes due to elevated LDH activity, which stimulates NDRG3 expression by increasing lactate generation, followed by cell growth in animals with metabolic disorders [ 52 ]. These compensatory mechanisms are activated in order to prevent heart failure [ 52 ]. In our current study, less pronounced cardiac hypertrophy signs demonstrated in animals fed the 5:1 diet, which was characterized by a higher n-3 PUFA content, led to the assumption that this effect was due to the increased myocardial LDHB expression.…”

Section: Discussionmentioning

confidence: 99%

Effects of Three-Month Feeding High Fat Diets with Different Fatty Acid Composition on Myocardial Proteome in Mice

et al. 2021

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Westernized diet is characterized by a high content of saturated fatty acids (SFA) and a low level of omega-3 polyunsaturated fatty acids (PUFA), often accompanied by an imbalance in the omega-6/omega-3 PUFA ratio. Since increased intake of SFA and n-6 PUFA is considered as a cardiovascular disease risk factor, this study was conducted to determine whether a three-month dietary supplementation of high-fat diets (HFDs) with saturated fatty acids and a significant proportion of various n-6 and n-3 PUFA ratios would affect the architecture and protein expression patterns of the murine heart. Therefore, three HFD (n = 6) feeding groups: rich in SFA, dominated by PUFA with the n-6/n-3–14:1, and n-6/n-3–5:1, ratios were compared to animals fed standard mouse chow. For this purpose, we performed two-dimensional electrophoresis with MALDI-ToF mass spectrometry-based identification of differentially expressed cardiac proteins, and a histological examination of cardiac morphology. The results indicated that mice fed with all HFDs developed signs of hypertrophy and cardiac fibrosis. Animals fed SFA-rich HFD manifested the most severe cardiac hypertrophy and fibrosis lesions, whereas less pronounced changes were observed in the group of animals that ingested the highest amount of omega-3 FA. In general, all HFDs, regardless of FA composition, evoked a comparable pattern of cardiac protein changes and affected the following biological processes: lipid metabolism and FA β-oxidation, glycolysis, TCA cycle, respiratory chain, myocardium contractility, oxidative stress and PUFA eicosanoid metabolism. However, it should be noted that three proteins, namely IDH3A, LDHB, and AK1, were affected differently by various FA contents. High expression of these myocardial proteins found in the group of animals fed a HFD with the highest n-3 PUFA content could be closely related to the observed development of hypertrophy.

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Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Cited by 53 publications

References 53 publications

Intraventricular pressure gradients change during the development of left ventricular hypertrophy: Effect of salvianolic acid B and beta-blocker

Intraventricular pressure gradients change during the development of left ventricular hypertrophy: Effect of salvianolic acid B and beta-blocker

An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T)

Effects of Three-Month Feeding High Fat Diets with Different Fatty Acid Composition on Myocardial Proteome in Mice

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