Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease

Med, Journal Year: 2024, Volume and Issue: 5(1), P. 10 - 31

Published: Jan. 1, 2024

Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion pathophysiological substrate ischemic disease. Improvements in prevention treatment have reduced mortality developed countries over last decades, but further progress now stagnant, morbidity from developing are increasing. Significant problems remain to be resolved require a better understanding. The present review attempts briefly summarize state art myocardial research, with view on both its coronary vascular aspects, define cutting edges where mechanistic knowledge needed facilitate translation clinical practice.

Language: Английский

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Cyclin-dependent protein kinases and cell cycle regulation in biology and disease

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 12, 2025

Abstract Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as kinases able drive division. In reality, human genome contains 20 different CDKs, which can be divided in at least three sub-family with functions, mechanisms regulation, expression patterns and subcellular localization. Most these play fundamental roles normal physiology eucaryotic cells; therefore, their deregulation is associated onset and/or progression multiple disease including but not limited neoplastic neurodegenerative conditions. Here, we describe functions categorized into main functional groups they classified, highlighting most relevant pathways that functions. We then discuss potential CDKs pathologies, a particular focus on cancer, have extensively studied explored therapeutic targets. Finally, how inhibitors become standard therapies selected cancers propose novel ways investigation export targeting from cancer other chronic diseases. hope effort made collecting all available information both prominent lesser-known CDK family members will help identify develop areas research improve lives patients affected by debilitating

Language: Английский

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LPA ₂ Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction

Circulation Research, Journal Year: 2022, Volume and Issue: 131(5), P. 388 - 403

Published: Aug. 3, 2022

Rationale: Myocardial infarction (MI) is one of the most dangerous adverse cardiovascular events. Our previous study found that lysophosphatidic acid (LPA) increased in human peripheral blood after MI, and LPA has a protective effect on survival proliferation various cell types. However, role its receptors MI less understood. Objectives: To unknown heart during MI. Methods Results: In this study, we mice also had elevated level blood, as well cardiac expression receptor 2 early stages With adult neonate models global Lpar2 knockout ( -KO) mice, deficiency vascular leak leading to disruption homeostasis, so impaired function mortality. Histological examination revealed larger scar size, fibrosis, reduced density -KO mice. Furthermore, attenuated flow recovery femoral artery ligation with decreased gastrocnemius. was mainly expressed altered endothelial cells use endothelial-specific phenocopied Additionally, adenovirus- pharmacologically activated significantly improved function, formation, alleviated mortality by maintaining homeostasis owing protecting vessels from leakage. Mechanistic studies demonstrated LPA-LPA signaling could promote through PI3K-Akt/PLC-Raf1-Erk pathway enhanced tube formation via PKD1-CD36 signaling. Conclusions: results indicate promotes angiogenesis maintains which vital for restoring repairing tissue ischemic injuries. Targeting signal might have clinical therapeutic potential protect injury.

Language: Английский

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CCND2 Modified mRNA Activates Cell Cycle of Cardiomyocytes in Hearts With Myocardial Infarction in Mice and Pigs

Circulation Research, Journal Year: 2023, Volume and Issue: 133(6), P. 484 - 504

Published: Aug. 11, 2023

Experiments in mammalian models of cardiac injury suggest that the cardiomyocyte-specific overexpression CCND2 (cyclin D2, humans) improves recovery from myocardial infarction (MI). The primary objective this investigation was to demonstrate our specific modified mRNA translation system (SMRTs) can induce expression cardiomyocytes and replicate benefits observed other studies for repair.

Language: Английский

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Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Circulation, Journal Year: 2024, Volume and Issue: 149(20), P. 1598 - 1610

Published: May 13, 2024

Defining mechanisms of cardiomyocyte proliferation should guide the understanding endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In neonatal heart, energy metabolic reprogramming (phenotypic alteration glucose, fatty acid, amino acid metabolism) parallels cell cycle arrest cardiomyocytes. The occurring shortly after birth is associated with alterations in blood oxygen levels, substrate availability, hemodynamic stress, hormone release. adult infarction causes but these changes cannot stimulate sufficient replace those lost by ischemic injury. Some putative pro-proliferative interventions can induce reprogramming. Recent data show that altering enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] partially reverse promotes proliferation. How regulates not clearly defined. possible involve biosynthetic pathways from glycolysis shunts epigenetic regulation induced intermediates. Metabolic manipulation represent a new approach regeneration; however, efficacy manipulations requires optimization, molecular targets need be this review, we summarize features, triggers, regulatory networks responsible discuss current critical determinant

Language: Английский

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Indole‐3‐Lactic Acid Inhibits Doxorubicin‐Induced Ferroptosis Through Activating Aryl Hydrocarbon Receptor/Nrf2 Signalling Pathway

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

ABSTRACT The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which primarily attributed interaction with iron in mitochondria, leading lipid peroxidation and myocardial ferroptosis. This study aimed investigate the role gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, ferroptosis were assessed vivo. cardioprotective effects mechanisms ILA explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) bulk RNA‐seq, further validated Nrf2 knockout mice. findings revealed that DOX treatment disrupted microbiota, significantly reducing levels tryptophan metabolite ILA. In DIC models, supplementation markedly improved cardiac reduced collagen deposition, mitigated atrophy. snRNA‐seq analyses indicated played a crucial Experimental data demonstrated decreased both mice DOX‐treated H9C2 cells, evidenced by restoration GPX4 SLC7A11 reduction ACSL4. Mechanistically, functions as ligand for aryl hydrocarbon receptor (AhR), upregulation expression. protective against abolished silencing AhR. Moreover, beneficial on eliminated Nrf2‐deficient conclusion, exerts therapeutic inhibiting through activation AhR/Nrf2 signalling pathway. Identifying microbial could offer viable strategies DIC.

Language: Английский

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Metabolic Determinants of Cardiomyocyte Proliferation

Stem Cells, Journal Year: 2022, Volume and Issue: 40(5), P. 458 - 467

Published: March 5, 2022

The adult mammalian heart is recalcitrant to regeneration after injury, in part due the postmitotic nature of cardiomyocytes. Accumulating evidence suggests that cardiomyocyte proliferation fetal or neonatal mammals and regenerative non-mammalian models depends on a conducive metabolic state. Results from numerous studies hearts indicate conditions relatively low fatty acid oxidation, reactive oxygen species generation, high glycolysis are required for induction proliferation. Glycolysis appears particularly important because it provides branchpoint metabolites several biosynthetic pathways essential synthesis nucleotides nucleotide sugars, amino acids, glycerophospholipids, all which daughter cell formation. In addition, proliferative phenotype supported by tensions through actions critical transcription factors, coactivators, signaling promote more glycolytic phenotype, such as hypoxia inducible factor 1α (Hif1α), Yes-associated protein (Yap), ErbB2. Interventions inhibit its integrated almost universally impair capacity. Furthermore, enzymes augment capacity phosphoenolpyruvate carboxykinase 2 pyruvate kinase M2 appear be amplifiers Collectively, these suggest acquisition sine qua non Further knowledge regulatory mechanisms control substrate partitioning coordinate biosynthesis with energy provision could leveraged prompt division cardiac repair.

Language: Английский

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Animal models to study cardiac regeneration

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 21(2), P. 89 - 105

Published: Aug. 14, 2023

Language: Английский

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One Endothelium-Targeted Combined Nucleic Acid Delivery System for Myocardial Infarction Therapy

ACS Nano, Journal Year: 2024, Volume and Issue: 18(11), P. 8107 - 8124

Published: March 5, 2024

Acute myocardial infarction (MI) and ischemic heart disease are the leading causes of failure mortality. Currently, research on MI treatment is focused angiogenic anti-inflammatory therapies. Although endothelial cells (ECs) critical for triggering inflammation angiogenesis, no approach has targeted them MI. In this study, we proposed a nonviral combined nucleic acid delivery system consisting an EC-specific polycation (CRPPR-grafted ethanolamine-modified poly(glycidyl methacrylate), CPC) that can efficiently codeliver siR-ICAM1 pCXCL12 Animals treated with combination therapy exhibited better cardiac function than those each alone. particular, CPC/siR-ICAM1 CPC/pCXCL12 significantly improved systolic function, responses, angiogenesis compared to control group. conclusion, CPC-based gene systems show impressive performance in provide programmed strategy development codelivery various EC-related diseases.

Language: Английский

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Morroniside induces cardiomyocyte cell cycle activity and promotes cardiac repair after myocardial infarction in adult rats

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

Introduction: Acute myocardial infarction (AMI) is characterized by the loss of cardiomyocytes, which impairs cardiac function and eventually leads to heart failure. The induction cardiomyocyte cell cycle activity provides a new treatment strategy for repair damage. Our previous study demonstrated that morroniside exerts cardioprotective effects. This investigated effects underlying mechanisms action on following AMI. Methods: Neonatal rat cardiomyocytes (NRCMs) were isolated exposed oxygen-glucose deprivation (OGD) in vitro . A model AMI was established ligation left anterior descending coronary artery (LAD) vivo Immunofluorescence staining performed detect newly generated cardiomyocytes. Western blotting assess expression cycle-related proteins. Electrocardiography (ECG) used examine pathological Q waves. Masson’s trichrome wheat germ agglutinin (WGA) assessed fibrosis hypertrophy. Results: results showed induced increased levels proteins, including cyclin D1, CDK4, A2, B1, both Moreover, reduced remodeling. Discussion: In conclusion, our stimulates adult rats, these may be related upregulation

Language: Английский

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