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Journal of Cellular and Molecular... May 2024Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly... (Review)
Review
Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.
Topics: Humans; Animals; Bone Morphogenetic Proteins; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Cardiomyopathies; Myocardium; Myocytes, Cardiac; Apoptosis
PubMed: 38760897
DOI: 10.1111/jcmm.18324 -
Phytomedicine : International Journal... Jul 2024JinLiDa granules (JLD) is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus with Qi and Yin deficiency. Clinical evidence has shown that JLD...
BACKGROUND
JinLiDa granules (JLD) is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus with Qi and Yin deficiency. Clinical evidence has shown that JLD can alleviate diabetic cardiomyopathy, but the exact mechanism is not yet clear.
PURPOSE
The purpose of this study was to examine the potential role and mechanism of JLD in the treatment of diabetic cardiomyopathy through network pharmacological analysis and basic experiments.
METHODS
The targets of JLD associated with diabetic cardiomyopathy were examined by network pharmacology. Protein interaction analysis was performed on the targets, and the associated pathways were searched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Diabetic mice were treated with low or high doses of JLD by gavage, and AC16 and H9C2 cardiomyocytes exposed to high-glucose conditions were treated with JLD. The analysis results were verified by various experimental techniques to examine molecular mechanisms.
RESULTS
Network pharmacological analysis revealed that JLD acted on the tumor suppressor p53 (TP53) during inflammation and fibrosis associated with diabetic cardiomyopathy. The results of basic experiments showed that after JLD treatment, ventricular wall thickening in diabetic mouse hearts was attenuated, cardiac hypertrophy and myocardial inflammation were alleviated, and the expression of cardiac hypertrophy- and inflammation-related factors in cardiomyocytes exposed to a high-glucose environment was decreased. Cardiomyocyte morphology also improved after JLD treatment. TP53 expression and the tumor necrosis factor (TNF) and transforming growth factor beta-1 (TGFβ1) signaling pathways were significantly altered, and inhibiting TP53 expression effectively alleviated the activation of the TNF and TGFβ1 signaling pathways under high glucose conditions. Overexpression of TP53 activated these signaling pathways.
CONCLUSIONS
JLD acted on TP53 to regulate the TNF and TGFβ1 signaling pathways, effectively alleviating cardiomyocyte hypertrophy and inflammation in high glucose and diabetic conditions. Our study provides a solid foundation for the future treatment of diabetic cardiomyopathy with JLD.
Topics: Animals; Diabetic Cardiomyopathies; Drugs, Chinese Herbal; Tumor Suppressor Protein p53; Cardiomegaly; Mice; Diabetes Mellitus, Experimental; Male; Transforming Growth Factor beta1; Myocytes, Cardiac; Mice, Inbred C57BL; Inflammation; Fibrosis; Cell Line; Rats; Tumor Necrosis Factor-alpha; Network Pharmacology; Signal Transduction; Diabetes Mellitus, Type 2
PubMed: 38759318
DOI: 10.1016/j.phymed.2024.155659 -
Gene Sep 2024Diabetic cardiomyopathy (DCM) is a special type of cardiovascular disease, termed as a situation of abnormal myocardial structure and function that occurs in diabetic...
BACKGROUND
Diabetic cardiomyopathy (DCM) is a special type of cardiovascular disease, termed as a situation of abnormal myocardial structure and function that occurs in diabetic patients. However, the most fundamental mechanisms of DCM have not been fully explicated, and useful targets for the therapeutic strategies still need to be explored.
METHODS
In the present study, we combined bioinformatics analysis and in vitro experiments throughout the process of DCM. Differentially Expressed Genes (DEGs) analysis was performed and the weighted gene co-expression network analysis (WGCNA) was constructed to determine the crucial genes that were tightly connected to DCM. Additionally, Functional enrichment analysis was conducted to define biological pathways. To identify the specific molecular mechanism, the human cardiomyocyte cell line (AC16) was stimulated by high glucose (HG, 50 mM D-glucose) and used to imitate DCM condition. Then, we tentatively examined the effect of high glucose on cardiomyocytes, the expression levels of crucial genes were further validated by in vitro experiments.
RESULTS
Generally, NPPA, IGFBP5, SERPINE1, and C3 emerged as potential therapeutic targets. Functional enrichment analysis performed by bioinformatics indicated that the pathogenesis of DCM is mainly related to heart muscle contraction and calcium (Ca) release activation. In vitro, we discovered that high glucose treatment induced cardiomyocyte injury and exacerbated mitochondrial dysfunction remarkably.
CONCLUSION
Our research defined four crucial genes, as well as determined that mitochondrial function impairment compromises calcium homeostasis ultimately resulting in contractile dysfunction is a central contributor to DCM progression. Hopefully, this study will offer more effective biomarkers for DCM diagnosis and treatment.
Topics: Diabetic Cardiomyopathies; Humans; Myocytes, Cardiac; Glucose; Cell Line; Plasminogen Activator Inhibitor 1; Computational Biology; Gene Regulatory Networks; Gene Expression Profiling; Mitochondria; Calcium
PubMed: 38754569
DOI: 10.1016/j.gene.2024.148563 -
Cardiovascular Diabetology May 2024Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD,... (Review)
Review
Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.
Topics: Humans; Macrophages; Diabetic Cardiomyopathies; Animals; Oxidative Stress; Signal Transduction; Fibrosis; Anti-Inflammatory Agents; Myocardium; Insulin Resistance; Inflammation Mediators; Molecular Targeted Therapy
PubMed: 38750502
DOI: 10.1186/s12933-024-02273-4 -
International Heart Journal May 2024Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of...
Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe/MDA/ROS, and expression of interleukin (IL)-1β/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.
Topics: Ferroptosis; Animals; Myocytes, Cardiac; Mice; Perilipin-5; Diabetic Cardiomyopathies; NF-kappa B; Reactive Oxygen Species; Cell Survival; Palmitic Acid; Signal Transduction
PubMed: 38749744
DOI: 10.1536/ihj.24-002 -
BMC Medicine May 2024Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an...
BACKGROUND
Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice.
METHODS
Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined "pure" DbCM when SBHF is associated solely with T2D and "mixed" SBHF when other medical conditions can contribute to SBHF. "Pure" DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF.
RESULTS
Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with "mixed" SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of "pure" DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study.
CONCLUSIONS
Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Diabetic Cardiomyopathies; Middle Aged; Retrospective Studies; Prevalence; Aged; Academic Medical Centers; Echocardiography; Adult; Heart Failure
PubMed: 38745169
DOI: 10.1186/s12916-024-03401-3 -
Fitoterapia Jul 2024Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent... (Review)
Review
Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent non-communicable disease. Hyperglycemia in DM is a known risk factor for cardiovascular diseases (CVDs), which substantially impact global mortality rates. This review examines the potential effects of naringin, a citrus flavonoid, on both DM and its associated cardiovascular complications, including conditions like diabetic cardiomyopathy. The safety profile of naringin is summarized based on various pre-clinical studies. The data for this review was gathered from diverse electronic databases, including Medline, PubMed, ScienceDirect, SpringerLink, Google Scholar, and Emerald Insight. Multiple pre-clinical studies have demonstrated that naringin exerts hypoglycemic and cardioprotective effects by targeting various vascular mechanisms. Specifically, research indicates that naringin down-regulates the renin-angiotensin and oxidative stress systems while concurrently upregulating β-cell and immune system functions. Clinical trial outcomes also support the therapeutic potential of naringin in managing hyperglycemic states and associated cardiovascular issues. Moreover, toxicity studies have confirmed the safety of naringin in animal models, suggesting its potential for safe administration in humans. In conclusion, naringin emerges as a promising natural candidate for both antidiabetic and cardioprotective purposes, offering potential improvements in health outcomes. While naringin presents a new avenue for therapies targeting DM and CVDs, additional controlled and long-term clinical trials are necessary to validate its efficacy and safety for human use.
Topics: Flavanones; Humans; Animals; Cardiotonic Agents; Hypoglycemic Agents; Diabetes Mellitus; Cardiovascular Diseases; Diabetic Cardiomyopathies; Oxidative Stress; Renin-Angiotensin System
PubMed: 38740344
DOI: 10.1016/j.fitote.2024.106011 -
International Journal of Molecular... May 2024Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly... (Review)
Review
Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle-a well-balanced diet and physical activity. There is also a group of compounds-including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others-that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.
Topics: Humans; Diabetic Cardiomyopathies; Hypoglycemic Agents; Oxidative Stress; Antioxidants; Diabetes Mellitus; Animals
PubMed: 38732253
DOI: 10.3390/ijms25095027 -
Cardiovascular Diabetology May 2024Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct...
Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.
Topics: Animals; Humans; Male; Mice; Cells, Cultured; Coronary Circulation; Diabetic Cardiomyopathies; Disease Models, Animal; Dynamins; Endothelial Cells; Ferroptosis; Intracellular Signaling Peptides and Proteins; Mitochondria, Heart; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 38724987
DOI: 10.1186/s12933-024-02254-7 -
Phytomedicine : International Journal... Jul 2024As a common complication of diabetes, diabetic cardiomyopathy (DCM) often leads to further damage to the heart muscle. Curcumin has been proven to have a variety of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
As a common complication of diabetes, diabetic cardiomyopathy (DCM) often leads to further damage to the heart muscle. Curcumin has been proven to have a variety of cardioprotective effects, however, the protective effect against DCM has not been systematically reviewed.
PURPOSE
In this study, we aimed to analyze the preclinical (animal model) evidence of curcumin's therapeutic effects in DCM.
METHODS
Eight databases and two registry systems were searched from the time of library construction to 1 November 2023. We performed rigorous data extraction and quality assessment. The included studies' methodological quality was appraised using the SYRCLE RoB tool, statistical analyses were carried out using RevMan 5.4 software, and Funnel plots and Egger's test were performed using Stata 17.0 software to assess publication bias.
RESULTS
This study included 32 trials with a total of 681 animals. Meta-analysis showed that curcumin significantly improved cardiac function indices (LVEF, LVFS, and LVSd) (p < 0.01), decreased markers of myocardial injury, HW/BW ratio, and randomized blood glucose compared to the control group, in addition to showing beneficial effects on mechanistic indices of myocardial oxidation, inflammation, apoptosis, and autophagy (p < 0.05).
CONCLUSIONS
Curcumin may exert cardioprotective effects in DCM through its antioxidant, anti-inflammatory, autophagy-enhancing, and anti-apoptotic effects. Its protective effect is proportional to the dose, and the efficacy may be further increased at a concentration of more than 200 mg/kg, and further validation is needed.
Topics: Curcumin; Diabetic Cardiomyopathies; Animals; Cardiotonic Agents; Apoptosis
PubMed: 38723524
DOI: 10.1016/j.phymed.2024.155619