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Pharmacological Research Jul 2024Diabetic cardiomyopathy (DCM) is a major complication of diabetes and is characterized by left ventricular dysfunction. Currently, there is a lack of effective...
Diabetic cardiomyopathy (DCM) is a major complication of diabetes and is characterized by left ventricular dysfunction. Currently, there is a lack of effective treatments for DCM. Ubiquitin-specific protease 7 (USP7) plays a key role in various diseases. However, whether USP7 is involved in DCM has not been established. In this study, we demonstrated that USP7 was upregulated in diabetic mouse hearts and NMCMs co-treated with HG+PA or H9c2 cells treated with PA. Abnormalities in diabetic heart morphology and function were reversed by USP7 silencing through conditional gene knockout or chemical inhibition. Proteomic analysis coupled with biochemical validation confirmed that PCG1β was one of the direct protein substrates of USP7 and aggravated myocardial damage through coactivation of the PPARα signaling pathway. USP7 silencing restored the expression of fatty acid metabolism-related proteins and restored mitochondrial homeostasis by inhibiting mitochondrial fission and promoting fusion events. Similar effects were also observed in vitro. Our data demonstrated that USP7 promoted cardiometabolic metabolism disorders and mitochondrial homeostasis dysfunction via stabilizing PCG1β and suggested that silencing USP7 may be a therapeutic strategy for DCM.
Topics: Animals; Ubiquitin-Specific Peptidase 7; Homeostasis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Mitochondria, Heart; Cell Line; Mice, Knockout; Rats; Mitochondria; Humans
PubMed: 38815879
DOI: 10.1016/j.phrs.2024.107235 -
ESC Heart Failure May 2024In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations... (Review)
Review
In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.
PubMed: 38806171
DOI: 10.1002/ehf2.14857 -
Scientific Reports May 2024Despite its effectiveness in treating diabetic cardiomyopathy (DCM), Qigui Qiangxin Mixture (QGQXM) remains unclear in terms of its active ingredients and specific...
Despite its effectiveness in treating diabetic cardiomyopathy (DCM), Qigui Qiangxin Mixture (QGQXM) remains unclear in terms of its active ingredients and specific mechanism of action. The purpose of this study was to explore the active ingredients and mechanism of action of QGQXM in the treatment of DCM through the comprehensive strategy of serum pharmacology, network pharmacology and combined with experimental validation. The active ingredients of QGQXM were analyzed using Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q/TOF-MS). Network pharmacology was utilized to elucidate the mechanism of action of QGQXM for the treatment of DCM. Finally, in vivo validation was performed by intraperitoneal injection of STZ combined with high-fat feeding-induced DCM rat model. A total of 25 active compounds were identified in the drug-containing serum of rats, corresponding to 121 DCM-associated targets. GAPDH, TNF, AKT1, PPARG, EGFR, CASP3, and HIF1 were considered as the core therapeutic targets. Enrichment analysis showed that QGQXM mainly treats DCM by regulating PI3K-AKT, MAPK, mTOR, Insulin, Insulin resistance, and Apoptosis signaling pathways. Animal experiments showed that QGQXM improved cardiac function, attenuated the degree of cardiomyocyte injury and fibrosis, and inhibited apoptosis in DCM rats. Meanwhile, QGQXM also activated the PI3K/AKT signaling pathway, up-regulated Bcl-2, and down-regulated Caspase9, which may be an intrinsic mechanism for its anti-apoptotic effect. This study preliminarily elucidated the mechanism of QGQXM in the treatment of DCM and provided candidate compounds for the development of new drugs for DCM.
Topics: Animals; Drugs, Chinese Herbal; Diabetic Cardiomyopathies; Network Pharmacology; Rats; Male; Chromatography, High Pressure Liquid; Rats, Sprague-Dawley; Disease Models, Animal; Mass Spectrometry; Signal Transduction; Diabetes Mellitus, Experimental
PubMed: 38802644
DOI: 10.1038/s41598-024-63088-7 -
Journal of Translational Medicine May 2024Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure....
BACKGROUND
Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown.
METHODS
The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms.
RESULTS
We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM.
CONCLUSIONS
Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.
Topics: Animals; Female; Humans; Male; Mice; Middle Aged; Apoptosis; Diabetic Cardiomyopathies; DNA, Mitochondrial; Fibroblasts; Fibrosis; Interleukin-1; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Signal Transduction; Sirtuin 1
PubMed: 38790051
DOI: 10.1186/s12967-024-05250-3 -
Cellular and Molecular Life Sciences :... May 2024Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis...
Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.
Topics: Phosphofructokinase-2; Animals; Diabetic Cardiomyopathies; Ubiquitination; Mice; GTP Phosphohydrolases; Myocytes, Cardiac; Male; Oxidative Stress; Apoptosis; Myocardium; Mice, Inbred C57BL; Diabetes Mellitus, Type 2; Glycolysis; Humans; Protein Stability
PubMed: 38777955
DOI: 10.1007/s00018-024-05257-5 -
Biomedicine & Pharmacotherapy =... Jun 2024Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The... (Review)
Review
Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.
Topics: Diabetic Cardiomyopathies; Humans; Autophagy; Animals; Signal Transduction
PubMed: 38776677
DOI: 10.1016/j.biopha.2024.116790 -
Frontiers in Immunology 2024This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy... (Review)
Review
This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.
Topics: Diabetic Cardiomyopathies; Humans; Macrophages; Animals; Hypoglycemic Agents; Epigenesis, Genetic
PubMed: 38774880
DOI: 10.3389/fimmu.2024.1393392 -
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