FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression DOI Creative Commons
Dezhong Wang, Yuan Yin, Shu‐Yi Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: March 24, 2021

Abstract As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating is potential therapeutic target for DCM. We treatment variant (FGF1 ∆HBS ) reduced proliferative potency prevented diabetes-induced cardiac injury remodeling restored function. RNA-Seq results obtained from the tissues db/db mice showed significant increase expression anti-oxidative genes decrease Nur77 by treatment. Both vivo vitro studies indicate exerted these beneficial effects markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation cytochrome c leakage enhancing respiration rate β-oxidation 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all which not observed AMPK null mice. The favorable activity properties testify its promising use DCM disorders.

Language: Английский

Streptozotocin-Induced Type 1 and 2 Diabetes Mellitus Mouse Models Show Different Functional, Cellular and Molecular Patterns of Diabetic Cardiomyopathy DOI Open Access
Fabiola Marino, Nadia Salerno, Mariangela Scalise

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1132 - 1132

Published: Jan. 6, 2023

The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has widely used to produce experimental both type 1 2 DM (T1DM T2DM). Here, we compared these two for their effects on cardiac structure, function transcriptome. Different doses STZ diet chows were generate T1DM T2DM C57BL/6J mice. Normal euglycemic nonobese sex- age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR RNA-seq employed compare hearts from the three animal groups. STZ-induced affected left ventricular myocardial performance differently. displayed exaggerated apoptotic cardiomyocyte (CM) death reactive hypertrophy fibrosis, along with increased oxidative stress, CM DNA damage senescence, when whole transcriptome In conclusion, mouse showed significant differences remodeling, These could be key relevance choosing an model study specific features DCM.

Language: Английский

Citations

50
Mitophagy for cardioprotection DOI Creative Commons
Allen Sam Titus, Eun‐Ah Sung,

Daniela Zablocki

et al.

Basic Research in Cardiology, Journal Year: 2023, Volume and Issue: 118(1)

Published: Oct. 5, 2023

Abstract Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control including fusion and fission, degradation, biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are central organelle for maintaining cardiac function. Since adult cardiomyocytes humans rarely divide, number dysfunctional cannot easily be diluted through cell division. Thus, efficient degradation crucial to cellular Mitophagy, a specific form autophagy, major mechanism which damaged or unnecessary targeted eliminated. Mitophagy active at baseline response stress, plays an essential role cardiomyocytes. mediated multiple mechanisms heart, each these can partially compensate loss another mechanism. However, insufficient levels mitophagy eventually lead dysfunction development heart failure. In this review, we discuss molecular pathophysiology, with focus on recent findings field.

Language: Английский

Citations

49
USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart DOI Open Access
Saiyang Xie,

Shi‐qiang Liu,

Tong Zhang

et al.

Circulation, Journal Year: 2023, Volume and Issue: 149(9), P. 684 - 706

Published: Nov. 23, 2023

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role therapeutic value USP28 (ubiquitin-specific protease 28) on metabolic vulnerability cardiomyopathy. METHODS: type 2 mouse model was established using db/db leptin receptor–deficient mice high-fat diet/streptozotocin–induced mice. Cardiac-specific knockout in background generated by crossbreeding db/m Myh6-Cre + /USP28 fl/fl Recombinant adeno-associated virus serotype 9 carrying under troponin T promoter injected into High glucose plus palmitic acid–incubated neonatal rat ventricular myocytes human induced pluripotent stem cell-derived cardiomyocytes were used imitate vitro. molecular mechanism explored through RNA sequencing, immunoprecipitation mass spectrometry analysis, protein pull-down, chromatin assay. RESULTS: Microarray profiling UPS (ubiquitin-proteasome system) basis hearts patients’ demonstrated that ventricle presented a significant reduction expression. Diabetic exhibited more severe progressive dysfunction, lipid accumulation, mitochondrial disarrangement, compared their controls. On other hand, overexpression improved systolic diastolic ameliorated hypertrophy fibrosis heart. Adeno-associated 9-USP28 also less storage, reduced reactive oxygen species formation, impairment tissues than 9-null As result, attenuated remodeling These results confirmed cell–derived cardiomyocytes. assays, pull-down assay mechanistically revealed directly interacted PPARα (peroxisome proliferator–activated receptor α), deubiquitinating stabilizing (Lys152) promote Mfn2 (mitofusin 2) transcription, thereby impeding morphofunctional defects. However, such cardioprotective benefits largely abrogated deletion conditional loss-of-function Mfn2. CONCLUSIONS: Our findings provide USP28-modulated mitochondria homeostasis involves PPARα-Mfn2 axis hearts, suggesting activation or targeting represents strategy for

Language: Английский

Citations

43
Pyroptosis in health and disease: mechanisms, regulation and clinical perspective DOI Creative Commons
Yifan Liu,

Renjie Pan,

Yuzhen Ouyang

et al.

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

Published: Sept. 20, 2024

Language: Английский

Citations

40
The signaling pathways of selected traditional Chinese medicine prescriptions and their metabolites in the treatment of diabetic cardiomyopathy: a review DOI Creative Commons
Wencan Li, Xiang Liu, Zheng Liu

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 3, 2024

Diabetic cardiomyopathy (DCM) is a myocardial-specific microvascular disease caused by diabetes that affects the structure and function of heart considered to be leading cause morbidity death in patients with diabetes. Currently, there no specific treatment or preventive drug for DCM, an urgent need develop new drugs treat DCM. Traditional Chinese medicine (TCM) has rich experience its characteristics multi-target, multi-pathway, multi-component, few side effects can effectively deal complexity long-term nature Growing evidence suggests myocardial fibrosis, inflammation, oxidative stress, apoptosis, cardiac hypertrophy, advanced glycation end product deposition were main pathologic mechanisms According pathological mechanism this study revealed potential metabolites prescriptions TCM against DCM from perspective signaling pathways. The results showed TGF-β/Smad, NF-κB, PI3K/AKT, Nrf2, AMPK, NLRP3, Wnt/β-catenin pathways key aim was summarize update screen targets candidates provide ideas more experimental clinical use

Language: Английский

Citations

26
Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation DOI Creative Commons
Maoxiong Wu, Jing Tan, Zhengyu Cao

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 73, P. 103184 - 103184

Published: May 5, 2024

The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, precise roles Sirt5 in lipotoxicity DbCM remain unknown. This study aims elucidate role underlying mechanism context DbCM. expression myocardial was found be modestly elevated heart failure patients mice. Cardiac dysfunction, hypertrophy were exacerbated by ablation but improved forced Notably, deficiency impaired FAO without affecting capacity heart, leading accumulation intermediate metabolites, which mainly included medium- long-chain acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), crucial enzyme involved reconversion acyl-carnitines acyl-CoA facilitating FAO, functional succinylated substrate mediator Sirt5. Succinylation Lys424 CPT2 significantly increased deficiency, inactivation its enzymatic activity subsequent K424R mutation, mitigated succinylation modification, counteracted reduction mediated thereby attenuating knockout-induced impairment lipid deposition. impairs through CPT2. underscores potential therapeutic targets for addressing

Language: Английский

Citations

19
Predicting coronary heart disease in Chinese diabetics using machine learning DOI
Cai-Yi Ma, Yamei Luo, Tianyu Zhang

et al.

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 169, P. 107952 - 107952

Published: Jan. 5, 2024

Language: Английский

Citations

18
MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus DOI Creative Commons

Xiu Mei,

Kang Geng, Peng Wang

et al.

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: March 14, 2024

Abstract Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by multifaceted pathogenesis and limited therapeutic options. While lactate, byproduct of glycolysis, known be significantly elevated type 2 diabetes, its specific role DCM remains uncertain. This study reveals an abnormal upregulation monocarboxylate transporter 4 (MCT4) on the plasma membrane cardiomyocytes leading excessive lactate efflux from these cells. The disruption transport homeostasis perturbs intracellular lactate-pyruvate balance cardiomyocytes, resulting oxidative stress inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased augments histone H4K12 lactylation macrophages, facilitating infiltration within microenvironment. In vivo experiments have demonstrated inhibiting MCT4 effectively alleviates pathological damage, reduces macrophage infiltration, enhances cardiac function mice. Furthermore, clinical prediction model has been established, demonstrating notable association between peripheral blood levels diastolic dysfunction individuals with diabetes. underscores potential as prognostic biomarker for DCM. Ultimately, highlight pivotal involvement dysregulation energy metabolism macrophage-mediated inflammation These insights offer novel perspectives pave way development targeted strategies against this debilitating condition.

Language: Английский

Citations

18
KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy DOI Open Access
Ioannis D. Kyriazis, Matthew Hoffman,

Lea Gaignebet

et al.

Circulation Research, Journal Year: 2020, Volume and Issue: 128(3), P. 335 - 357

Published: Dec. 2, 2020

Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that diabetes associated with increased expression of KLF5 (Krüppel-like factor-5) PPARα (peroxisome proliferator-activated receptor) regulate lipid metabolism.

Language: Английский

Citations

104
The regulatory roles of p53 in cardiovascular health and disease DOI
Hongbo Men, He Cai,

Quanli Cheng

et al.

Cellular and Molecular Life Sciences, Journal Year: 2020, Volume and Issue: 78(5), P. 2001 - 2018

Published: Nov. 11, 2020

Language: Английский

Citations

98