The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms

Frontiers in Medicine, Journal Year: 2021, Volume and Issue: 8

Published: June 30, 2021

Individuals with diabetes mellitus (DM) disclose a higher incidence and poorer prognosis of heart failure (HF) than non-diabetic people, even in the absence other HF risk factors. The adverse impact on likely reflects an underlying "diabetic cardiomyopathy" (DM-CMP), which may by exacerbated left ventricular hypertrophy coronary artery disease (CAD). pathogenesis DM-CMP has been hot topic research since its first description is still under active investigation, as complex interplay among multiple mechanisms play role at systemic, myocardial, cellular/molecular levels. Among these, metabolic abnormalities such lipotoxicity glucotoxicity, mitochondrial damage dysfunction, oxidative stress, abnormal calcium signaling, inflammation, epigenetic factors, others. These disturbances predispose diabetic to extracellular remodeling hypertrophy, thus leading diastolic systolic dysfunction. This Review aims outline major pathophysiological changes myocardial cardiac functional derangement DM-CMP.

Language: Английский

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Glycosylation: mechanisms, biological functions and clinical implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 5, 2024

Protein post-translational modification (PTM) is a covalent process that occurs in proteins during or after translation through the addition removal of one more functional groups, and has profound effect on protein function. Glycosylation most common PTMs, which polysaccharides are transferred to specific amino acid residues by glycosyltransferases. A growing body evidence suggests glycosylation essential for unfolding various activities organisms, such as playing key role regulation function, cell adhesion immune escape. Aberrant also closely associated with development diseases. Abnormal patterns linked emergence health conditions, including cancer, inflammation, autoimmune disorders, several other However, underlying composition structure glycosylated have not been determined. It imperative fully understand internal differential expression glycosylation, incorporate advanced detection technologies keep knowledge advancing. Investigations clinical applications focused sensitive promising biomarkers, effective small molecule targeted drugs emerging vaccines. These studies provide new area novel therapeutic strategies based glycosylation.

Language: Английский

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Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

European Journal of Heart Failure, Journal Year: 2023, Volume and Issue: 25(8), P. 1199 - 1212

Published: July 12, 2023

The development of the foetal heart is driven by increased glucose uptake and activation mammalian target rapamycin (mTOR) hypoxia-inducible factor-1α (HIF-1α), which drives glycolysis. In contrast, healthy adult governed sirtuin-1 (SIRT1) adenosine monophosphate-activated protein kinase (AMPK), promote fatty-acid oxidation substantial mitochondrial ATP production required for survival in a high-workload normoxic environment. During cardiac injury, recapitulates signalling programme, (although adaptive short term) highly deleterious if sustained long periods time. Prolonged increases cardiomyocytes under stress leads to flux through hexosamine biosynthesis pathway; its endproduct - uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) functions as critical nutrient surplus sensor. UDP-GlcNAc post-translational modification known O-GlcNAcylation, rapidly reversibly modifies thousands intracellular proteins. Both O-GlcNAcylation phosphorylation act at serine/threonine residues, but whereas regulated hundreds specific kinases phosphatases, only two enzymes, O-GlcNAc transferase (OGT) O-GlcNAcase (OGA), adds or removes GlcNAc (N-acetylglucosamine), respectively, from Recapitulation programming failure (regardless diabetes) accompanied marked both experimentally clinically. Heightened impaired calcium kinetics contractile derangements, arrhythmias related voltage-gated sodium channels Ca2+ /calmodulin-dependent II, dysfunction, maladaptive hypertrophy, microvascular fibrosis cardiomyopathy. These effects can be prevented suppression achieved upregulation AMPK SIRT1 pharmacological inhibition OGT stimulation OGA. sodium-glucose cotransporter 2 (SGLT2) inhibitors on are reduced their cytoprotective reportedly abrogated action suppress blocked. Such an may represent one many mechanisms enhanced following SGLT2 cardiovascular benefits. observations, taken collectively, suggest that sensor (which acting concert with mTOR HIF-1α)

Language: Английский

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Research progress on post-translational modification of proteins and cardiovascular diseases

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: July 28, 2023

Abstract Cardiovascular diseases (CVDs) such as atherosclerosis, myocardial remodeling, ischemia-reperfusion (I/R) injury, heart failure, and oxidative stress are among the greatest threats to human health worldwide. pathogenesis has been studied for decades, influence of epigenetic changes on CVDs extensively studied. Post-translational modifications (PTMs), including phosphorylation, glycosylation, methylation, acetylation, ubiquitination, ubiquitin-like nitrification, play important roles in normal functioning cardiovascular system. Over past decade, with application high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), an increasing number novel acylation have discovered, propionylation, crotonylation, butyrylation, succinylation, lactylation, isonicotinylation. Each change protein conformation potential alter function lead CVDs, this process is usually reversible. This article summarizes mechanisms underlying several common PTMs involved occurrence development CVDs.

Language: Английский

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Protein O-GlcNAcylation in cardiovascular diseases

Acta Pharmacologica Sinica, Journal Year: 2022, Volume and Issue: 44(1), P. 8 - 18

Published: July 11, 2022

Language: Английский

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Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 571 - 571

Published: May 6, 2024

Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to hydroxyl terminus serine and threonine proteins. O-GlcNAcylation responsive cellular stress as reversible nuclear, mitochondrial cytoplasmic Mitochondrial proteins main targets key regulator homeostasis by directly regulating proteome or protein activity function. Disruption closely related dysfunction. More importantly, cardiac has been proven be protective harmful crucial for contractile function myocardial cell metabolism, imbalance plays role in pathogenesis cardiovascular diseases (CVDs). In this review, we will focus interactions between provide insights CVDs.

Language: Английский

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Regulation of protein O-GlcNAcylation by circadian, metabolic, and cellular signals

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 300(2), P. 105616 - 105616

Published: Dec. 29, 2023

O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a dynamic post-translational modification that regulates thousands of proteins and almost all cellular processes. Aberrant O-GlcNAcylation has been associated with numerous diseases, including cancer, neurodegenerative cardiovascular type 2 diabetes. highly nutrient-sensitive since it dependent on UDP-GlcNAc, the end product hexosamine biosynthetic pathway (HBP). We previously observed daily rhythmicity protein in Drosophila model sensitive to timing food consumption. showed circadian clock pivotal regulating rhythms given its control feeding-fasting cycle hence nutrient availability. Interestingly, we reported also modulates rhythm by molecular mechanisms beyond regulation consumption time. A large body work now indicates likely generalized status effector as responds various signals conditions, such ER stress, apoptosis, infection. In this review, summarize metabolic through availability, HBP enzymes, O-GlcNAc processing enzymes. discuss emerging roles clocks rhythm. Finally, provide an overview other or conditions impact O-GlcNAcylation. Many these pathways are themselves regulated and/or metabolism. Our review highlights importance maintaining optimal restricting eating activity active period under physiological provides insights into potential therapeutic targets homeostasis pathological conditions.

Language: Английский

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New Types of Post-Translational Modification of Proteins in Cardiovascular Diseases

Journal of Cardiovascular Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Post-translational modifications (PTMs), which are covalent alterations of proteins after their synthesis, critical for proper function and the maintenance cellular physiology. The significance PTMs in context cardiovascular diseases (CVDs) has been increasingly recognized due to potential influence protein stability, activity, localization, thereby affecting progression CVDs. identification understanding CVDs at molecular level vital discovery new biomarkers targets clinical interventions. This article provides a comprehensive overview role mechanisms types PTMs, such as acetylation, crotonylation, succinylation, S-nitrosylation, malonylation, S-palmitonylation, β-hydroxybutyrylation lactylation, CVDs, highlighting importance advancing diagnostic therapeutic approaches

Language: Английский

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The dual role of the hexosamine biosynthetic pathway in cardiac physiology and pathophysiology

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 24, 2022

The heart is a highly metabolic organ with extensive energy demands and hence relies on numerous fuel substrates including fatty acids glucose. However, oxidative stress natural by-product of metabolism that, in excess, can contribute towards DNA damage poly-ADP-ribose polymerase activation. This activation inhibits key glycolytic enzymes, subsequently shunting intermediates into non-oxidative glucose pathways such as the hexosamine biosynthetic pathway (HBP). In this review we provide evidence supporting dual role HBP, i.e. playing unique cardiac physiology pathophysiology where acute upregulation confers cardioprotection while chronic contributes to onset progression cardio-metabolic diseases diabetes, hypertrophy, ischemic disease, failure. Thus although HBP has emerged novel therapeutic target for conditions, proposed interventions need be applied context- pathology-specific manner avoid any potential drawbacks relatively low activity.

Language: Английский

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Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments

Cell Stress and Chaperones, Journal Year: 2023, Volume and Issue: 28(6), P. 641 - 655

Published: July 5, 2023

Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients the absence of other heart diseases such as ischemia and hypertension. Recent studies have defined numerous molecular interactions signaling events that may account for deleterious changes mitochondrial dynamics functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation fuel ATP synthesis, oxidative injury resulting increased ROS production antioxidant capacity, enhanced fission defective fusion, impaired mitophagy, blunted biogenesis are major signatures pathologies during cardiomyopathy. This review alterations underlying abnormalities associated with hyperglycemia discusses their influence on cardiomyocyte viability function. Based basic research findings clinical evidence, treatment standards impact function, well mitochondria-targeted therapies potential benefit patients, also summarized.

Language: Английский

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