PPAR control of metabolism and cardiovascular functions

Nature Reviews Cardiology, Journal Year: 2021, Volume and Issue: 18(12), P. 809 - 823

Published: June 14, 2021

Language: Английский

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Cardiac Energy Metabolism in Heart Failure

Circulation Research, Journal Year: 2021, Volume and Issue: 128(10), P. 1487 - 1513

Published: May 13, 2021

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, metabolic changes that occur failure are complex and dependent not only on type present but also co-existence common comorbidities such as obesity 2 diabetes. The failing faces an deficit, primarily because a decrease mitochondrial oxidative capacity. This is partly compensated for by increase ATP production from glycolysis. relative contribution different fuels changes, including glucose amino acid oxidation, ketone oxidation. oxidation fatty acids increases or decreases, depending For instance, associated with diabetes obesity, myocardial increases, while hypertension ischemia, decreases. Combined, these result becoming less efficient (ie, work/O consumed). alterations both glycolysis due transcriptional key enzymes involved pathways, well NAD redox state (NAD + nicotinamide adenine dinucleotide levels) metabolite signaling posttranslational epigenetic control expression genes encoding enzymes. fate glucose, beyond flux through pathology Of importance, pharmacological targeting pathways has emerged novel therapeutic approach improving efficiency, decreasing deficit function heart.

Language: Английский

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Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 20, 2023

Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays prominent role in cardiovascular diseases. From research history milestone events related to hypoxia development diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal spatial perspectives, encompassing occurrence progression (gradual decline concentration), acute chronic manifestations hypoxia, geographical characteristics (natural selection at high altitudes). Furthermore, signaling pathways are associated with natural rhythms, such as diurnal hibernation processes. In addition innate selection, it has been found epigenetics, postnatal factor, profoundly influences hypoxic response within system. Within this intricate process, interactions between different tissues organs system other systems context have established. Thus, time summarize construct multi-level regulatory framework mechanisms diseases for developing more therapeutic targets make reasonable advancements clinical research, including FDA-approved drugs ongoing trials, guide future practice field

Language: Английский

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‘Warburg effect’ controls tumor growth, bacterial, viral infections and immunity – Genetic deconstruction and therapeutic perspectives

Seminars in Cancer Biology, Journal Year: 2022, Volume and Issue: 86, P. 334 - 346

Published: July 9, 2022

The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections a variety biochemical pathways supporting the robust currently present on planet. First, we discuss how fermentative glycolysis, primitive metabolic pathway at emergence life, is instrumental rapid growth cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. 'Warburg effect', activated via Myc HIF-1 in response factors hypoxia, essential energetic which satisfies nutritional demands required genome replication. Second, key role lactic acid, end-product glycolysis able move across cell membranes both directions monocarboxylate transporting proteins (i.e., MCT1/4) contributing cell-pH homeostasis complex acidosis tumor microenvironment. Importantly lactate recycled multiple organs as major precursor gluconeogenesis energy source protecting animals harsh or oxygen restrictions. Third, revisit Warburg effect CRISPR-Cas9 disruption glucose-6-phosphate isomerase (GPI-KO) dehydrogenases (LDHA/B-DKO) two aggressive tumors (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression acid production reduces does not suppress due reactivation OXPHOS. In contrast, transporters MCT1/4 suppressed mTORC1, result intracellular acidosis. Finally, briefly current clinical developments MCT1 specific drug AZ3965, recent progress vivo MCT4 inhibitor, drugs very high potential future cancer applications.

Language: Английский

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Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(12), P. 812 - 829

Published: May 26, 2023

Language: Английский

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α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure

Cell Research, Journal Year: 2023, Volume and Issue: 33(9), P. 679 - 698

Published: July 13, 2023

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this in normal failing hearts remains unknown. Lactate a crucial energy substrate heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate Titin. We observed reduction K1897 mice patients heart failure. Loss K1897R knock-in reduces α-MHC-Titin leads impaired function. Furthermore, identified p300 Sirtuin 1 act as acyltransferase delactylase α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation lactylation, impairs worsens By contrast, upregulation concentration administering sodium inhibiting pivotal transporter cardiomyocytes can promote interaction, thereby alleviating In conclusion, dynamically regulated an important determinant overall Excessive efflux consumption may decrease intracellular level, which main cause reduced during myocardial injury. Our study reveals metabolism directly modulates function through lactate-dependent modification α-MHC.

Language: Английский

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Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase

Science, Journal Year: 2023, Volume and Issue: 379(6636), P. 996 - 1003

Published: March 10, 2023

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these frequently low affinity challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery (MIDAS) identify such interactions. Analysis 33 enzymes from human carbohydrate metabolism identified 830 interactions, including known regulators, substrates, products as well previously unreported functionally validated a subset isoform-specific inhibition lactate dehydrogenase by long-chain acyl–coenzyme A. Cell treatment fatty acids caused loss pyruvate-lactate interconversion dependent on isoform expression. These may contribute dynamic, tissue-specific metabolic flexibility enables growth survival in an ever-changing nutrient environment.

Language: Английский

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Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack

Hepatology, Journal Year: 2022, Volume and Issue: 77(1), P. 109 - 123

Published: Jan. 19, 2022

Background and Aims: Monocarboxylate transporter (MCT) 4 is a high‐affinity lactate that primarily involved in the maintenance of intracellular pH homeostasis highly expressed different tumors. However, role MCT4 modulating immune responses against HCC remains unknown. Approach Results: In this study, we demonstrated was overexpressed HCC, which associated with poor prognosis patients. Genetic or pharmacological inhibition using VB124 (a potent inhibitor) suppressed tumor growth immunocompetent mice model by enhancing CD8 + T cell infiltration cytotoxicity. Such improved immunotherapy response targeting due to combined consequences characterized alleviated acidification microenvironment elevated chemokine (C‐X‐C motif) ligand (CXCL) 9/CXCL10 secretion induced reactive oxygen species/NF‐κB signaling pathway. Combining therapeutic benefit anti–programmed death 1 prolonged survival. Moreover, higher expression observed tissues from nonresponder patients receiving neoadjuvant therapy toripalimab. Conclusions: Our results revealed exportation has tumor‐intrinsic function generating an immunosuppressive environment proof concept tailoring immunotherapeutic approaches.

Language: Английский

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Ketones and the Heart: Metabolic Principles and Therapeutic Implications

Circulation Research, Journal Year: 2023, Volume and Issue: 132(7), P. 882 - 898

Published: March 30, 2023

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone a critical cardiac fuel have diverse roles the regulation of cellular processes such as metabolism, inflammation, crosstalk multiple organs that mediate disease. This review focuses on role metabolism health disease with an emphasis therapeutic potential ketosis treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative contributes to dysfunction pathologic remodeling during development HF. Growing evidence supports adaptive HF promote normal function attenuate progression. Enhanced utilization is mediated increased availability due systemic autonomous upregulation ketolytic enzymes. Therapeutic strategies designed restore high-capacity show promise address deficits underpin progression However, mechanisms involved beneficial effects yet be defined represent important future lines inquiry. In addition use energy substrate oxidation, modulate myocardial glucose fatty acids, two vital substrates regulate hypertrophy. salutary may also include extra-cardiac modulating immune responses, reducing fibrosis, promoting angiogenesis vasodilation. Additional pleotropic signaling properties AcAc discussed including epigenetic protection against stress. Evidence benefit feasibility examined preclinical clinical studies. Finally, ongoing trials reviewed perspective translation therapeutics

Language: Английский

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Deranged Myocardial Fatty Acid Metabolism in Heart Failure

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(2), P. 996 - 996

Published: Jan. 17, 2022

The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial acid metabolism, such as energy production using fuel, for which it is known that coordinated control of uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important efficient adenosine triphosphate (ATP) without unwanted side effects. taken up by cardiomyocytes not only used substrates but also the synthesis triglycerides replacement reaction chains in cell membrane phospholipids. Alterations metabolism affect structure function heart. Recently, breakthrough studies have focused on key transcription factors signaling systems modify their functions. In this article, we reviewed latest research role pathogenesis failure provide an outlook future challenges.

Language: Английский

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