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1.
J Cell Mol Med ; 28(10): e18324, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38760897

RESUMEN

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.


Asunto(s)
Proteínas Morfogenéticas Óseas , Enfermedades Cardiovasculares , Diabetes Mellitus , Cardiomiopatías Diabéticas , Humanos , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Apoptosis
2.
Front Immunol ; 15: 1393392, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774880

RESUMEN

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.


Asunto(s)
Cardiomiopatías Diabéticas , Macrófagos , Cardiomiopatías Diabéticas/inmunología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Hipoglucemiantes/uso terapéutico , Epigénesis Genética
3.
J Transl Med ; 22(1): 494, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38790051

RESUMEN

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.


Asunto(s)
ADN Mitocondrial , Cardiomiopatías Diabéticas , Fibrosis , Interleucina-1 , Ratones Endogámicos C57BL , Miocitos Cardíacos , Animales , ADN Mitocondrial/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Humanos , Interleucina-1/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocardio/patología , Miocardio/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Persona de Mediana Edad , Ratones , Sirtuina 1/metabolismo , Apoptosis/efectos de los fármacos , Femenino
4.
Cell Mol Life Sci ; 81(1): 228, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38777955

RESUMEN

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.


Asunto(s)
Cardiomiopatías Diabéticas , GTP Fosfohidrolasas , Miocitos Cardíacos , Fosfofructoquinasa-2 , Ubiquitinación , Fosfofructoquinasa-2/metabolismo , Fosfofructoquinasa-2/genética , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/genética , Ratones , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Estrés Oxidativo , Apoptosis/genética , Miocardio/metabolismo , Miocardio/patología , Ratones Endogámicos C57BL , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Glucólisis , Humanos , Estabilidad Proteica
5.
Cardiovasc Diabetol ; 23(1): 160, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38715043

RESUMEN

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Fibrosis , Factores de Diferenciación de Crecimiento , Inflamasomas , Ratones Endogámicos C57BL , Miocitos Cardíacos , Piroptosis , Transducción de Señal , Animales , Piroptosis/efectos de los fármacos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Línea Celular , Inflamasomas/metabolismo , Masculino , Factores de Diferenciación de Crecimiento/metabolismo , Ratas , Glucemia/metabolismo , Ratones , Glucosa/metabolismo , Glucosa/toxicidad , Proteínas Morfogenéticas Óseas , PPAR alfa
6.
Cardiovasc Diabetol ; 23(1): 164, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724987

RESUMEN

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.


Asunto(s)
Cardiomiopatías Diabéticas , Dinaminas , Células Endoteliales , Ratones Endogámicos C57BL , Transducción de Señal , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/etiología , Humanos , Dinaminas/metabolismo , Dinaminas/genética , Masculino , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales/enzimología , Células Endoteliales/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ferroptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Células Cultivadas , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Mitocondrias Cardíacas/enzimología , Ratones , Procesamiento Proteico-Postraduccional , Circulación Coronaria , Péptidos y Proteínas de Señalización Intracelular
7.
J Transl Med ; 22(1): 390, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38671439

RESUMEN

BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.


Asunto(s)
Caveolina 3 , Cardiomiopatías Diabéticas , Complejo I de Transporte de Electrón , Mitocondrias , Miocitos Cardíacos , Animales , Masculino , Ratones , Apoptosis , Caveolina 3/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Complejo I de Transporte de Electrón/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología
8.
Eur J Pharmacol ; 974: 176609, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38677536

RESUMEN

PURPOSE: Diabetic cardiomyopathy is a prevalent cardiovascular complication of diabetes mellitus. This study aimed to investigate the effects of ginsenoside Rb1 (GRb1) on the diabetic myocardium. METHODS: Leptin receptor-deficient db/db mice and palmitic acid (PA)-treated cardiomyocyte models were utilized. Cardiac systolic and diastolic function, mitochondrial morphology, and respiratory chain function were determined. The expression of mitochondrial dynamics proteins was measured. Mitofusin 2 (Mfn2) overexpression and inhibition were achieved by lentiviral infection and small interfering RNA (siRNA) transfection. RESULTS: In comparison to non-diabetic mice, db/db mice exhibited significant increases in body weight, blood glucose, blood lipids, and cardiac free fatty acid levels. This was accompanied by myocardial hypertrophy and left ventricular diastolic dysfunction, which were significantly ameliorated by GRb1 intervention. Stimulation with PA increased oxidative stress and apoptosis, and decreased viability in H9c2 cardiomyocytes. PA also reduced sarcomere contractility and relaxation in adult mice ventricular myocytes. PA-induced cellular and mitochondrial damage were reversed with GRb1 treatment. The cardiac tissue of db/db mice and PA-treated cardiomyocytes exhibited a decrease in Mfn2 expression, which was markedly improved by GRb1. Mfn2 overexpression reversed PA-induced mitochondrial fragmentation and functional damage in cardiomyocytes, while inhibition of Mfn2 expression by siRNA transfection blocked the protective effects of GRb1. CONCLUSION: GRb1 alleviated myocardial lipid accumulation and mitochondrial injury, and attenuated ventricular diastolic dysfunction in diabetic mice. The regulation of Mfn2 was involved in the protective effects of GRb1 against lipotoxic myocardial injury.


Asunto(s)
Cardiomiopatías Diabéticas , GTP Fosfohidrolasas , Ginsenósidos , Miocitos Cardíacos , Animales , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Ratones , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Masculino , Ácido Palmítico/farmacología , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ratas , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Receptores de Leptina/deficiencia , Línea Celular , Ratones Endogámicos C57BL , Miocardio/patología , Miocardio/metabolismo
9.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167158, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38588780

RESUMEN

OBJECTIVES: Diabetic cardiomyopathy (DCM) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients, with its underlying mechanisms still elusive. This study aims to investigate the role of cholesterol-25-monooxygenase (CH25H) in T2DM induced cardiomyopathy. METHODS: High fat diet combined with streptozotocin (HFD/STZ) were used to establish a T2DM model. CH25H and its product 25-hydroxycholesterol (25HC) were detected in the hearts of T2DM model. Gain- or loss-of-function of CH25H were performed by receiving AAV9-cTNT-CH25H or CH25H knockout (CH25H-/-) mice with HFD/STZ treatment. Cardiac function was evaluated using echocardiography, and cardiac tissues were collected for immunoblot analysis, histological assessment and quantitative polymerase chain reaction (qPCR). Mitochondrial morphology and function were evaluated using transmission electron microscopy (TEM) and Seahorse XF Cell Mito Stress Test Kit. RNA-sequence analysis was performed to determine the molecular changes associated with CH25H deletion. RESULTS: CH25H and 25HC were significantly decreased in the hearts of T2DM mice. CH25H-/- mice treated with HFD/STZ exhibited impaired mitochondrial function and structure, increased lipid accumulation, and aggregated cardiac dysfunction. Conversely, T2DM mice receiving AAV9-CH25H displayed cardioprotective effects. Mechanistically, RNA sequencing and qPCR analysis revealed that CH25H deficiency decreased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target gene expression. Additionally, administration of ZLN005, a potent PGC-1α activator, partially protected against high glucose and palmitic acid induced mitochondria dysfunction and lipid accumulation in vitro. CONCLUSION: Our study provides compelling evidence supporting the protective role of CH25H in T2DM-induced cardiomyopathy. Furthermore, the regulation of PGC-1α may be intricately involved in this cardioprotective process.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Ratones Noqueados , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Ratones , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Esteroide Hidroxilasas/metabolismo , Esteroide Hidroxilasas/genética , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Hidroxicolesteroles/metabolismo , Miocardio/metabolismo , Miocardio/patología , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética
10.
Cardiovasc Diabetol ; 23(1): 139, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664790

RESUMEN

BACKGROUND: Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM's unique cell states and molecular landscape for targeted therapeutic interventions. METHODS: Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings. RESULTS: This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation. CONCLUSION: Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.


Asunto(s)
Cardiomiopatías Diabéticas , Análisis de la Célula Individual , Transcriptoma , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Animales , Perfilación de la Expresión Génica , Cromatina/metabolismo , Cromatina/genética , Ratones Endogámicos C57BL , Redes Reguladoras de Genes , Ensamble y Desensamble de Cromatina , Modelos Animales de Enfermedad , Masculino , RNA-Seq , Regulación de la Expresión Génica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/patología
11.
Biomed Pharmacother ; 174: 116589, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38636400

RESUMEN

Diabetic cardiomyopathy (DCM) is a common severe complication of diabetes that occurs independently of hypertension, coronary artery disease, and valvular cardiomyopathy, eventually leading to heart failure. Previous studies have reported that Tectorigenin (TEC) possesses extensive anti-inflammatory and anti-oxidative stress properties. In this present study, the impact of TEC on diabetic cardiomyopathy was examined. The model of DCM in mice was established with the combination of a high-fat diet and STZ treatment. Remarkably, TEC treatment significantly attenuated cardiac fibrosis and improved cardiac dysfunction. Concurrently, TEC was also found to mitigate hyperglycemia and hyperlipidemia in the DCM mouse. At the molecular level, TEC is involved in the activation of AMPK, both in vitro and in vivo, by enhancing its phosphorylation. This is achieved through the regulation of endothelial-mesenchymal transition via the AMPK/TGFß/Smad3 pathway. Furthermore, it was demonstrated that the level of ubiquitination of the adiponectin receptor 1 (AdipoR1) protein is associated with TEC-mediated improvement of cardiac dysfunction in DCM mice. Notably the substantial reduction of myocardial fibrosis. In conclusion, TEC improves cardiac fibrosis in DCM mice by modulating the AdipoR1/AMPK signaling pathway. These findings suggest that TEC could be an effective therapeutic agent for the treatment of diabetic cardiomyopathy.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Isoflavonas , Animales , Ratones , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/etiología , Dieta Alta en Grasa/efectos adversos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Ratones Endogámicos C57BL , Miocardio/patología , Miocardio/metabolismo , Receptores de Adiponectina/efectos de los fármacos , Receptores de Adiponectina/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Estreptozocina
12.
Stem Cell Res Ther ; 15(1): 120, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38659015

RESUMEN

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious health-threatening complication of diabetes mellitus characterized by myocardial fibrosis and abnormal cardiac function. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are a potential therapeutic tool for DCM and myocardial fibrosis via mechanisms such as the regulation of microRNA (miRNA) expression and inflammation. It remains unclear, however, whether hUC-MSC therapy has beneficial effects on cardiac function following different durations of diabetes and which mechanistic aspects of DCM are modulated by hUC-MSC administration at different stages of its development. This study aimed to investigate the therapeutic effects of intravenous administration of hUC-MSCs on DCM following different durations of hyperglycemia in an experimental male model of diabetes and to determine the effects on expression of candidate miRNAs, target mRNA and inflammatory mediators. METHODS: A male mouse model of diabetes was induced by multiple low-dose streptozotocin injections. The effects on severity of DCM of intravenous injections of hUC-MSCs and saline two weeks previously were compared at 10 and 18 weeks after diabetes induction. At both time-points, biochemical assays, echocardiography, histopathology, polymerase chain reaction (PCR), immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were used to analyze blood glucose, body weight, cardiac structure and function, degree of myocardial fibrosis and expression of fibrosis-related mRNA, miRNA and inflammatory mediators. RESULTS: Saline-treated diabetic male mice had impaired cardiac function and increased cardiac fibrosis after 10 and 18 weeks of diabetes. At both time-points, cardiac dysfunction and fibrosis were improved in hUC-MSC-treated mice. Pro-fibrotic indicators (α-SMA, collagen I, collagen III, Smad3, Smad4) were reduced and anti-fibrotic mediators (FGF-1, miRNA-133a) were increased in hearts of diabetic animals receiving hUC-MSCs compared to saline. Increased blood levels of pro-inflammatory cytokines (IL-6, TNF, IL-1ß) and increased cardiac expression of IL-6 were also observed in saline-treated mice and were reduced by hUC-MSCs at both time-points, but to a lesser degree at 18 weeks. CONCLUSION: Intravenous injection of hUC-MSCs ameliorated key functional and structural features of DCM in male mice with diabetes of shorter and longer duration. Mechanistically, these effects were associated with restoration of intra-myocardial expression of miRNA-133a and its target mRNA COL1AI as well as suppression of systemic and localized inflammatory mediators.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Fibrosis , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , MicroARNs , Miocardio , Cordón Umbilical , Animales , Humanos , Masculino , Ratones , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/terapia , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/genética , Fibrosis/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Miocardio/metabolismo , Miocardio/patología , Cordón Umbilical/citología , Cordón Umbilical/metabolismo
13.
Free Radic Biol Med ; 218: 149-165, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38570171

RESUMEN

Proper protein degradation is required for cellular protein homeostasis and organ function. Particularly, in post-mitotic cells, such as cardiomyocytes, unbalanced proteolysis due to inflammatory stimuli and oxidative stress contributes to organ dysfunction. To ensure appropriate protein turnover, eukaryotic cells exert two main degradation systems, the ubiquitin-proteasome-system and the autophagy-lysosome-pathway. It has been shown that proteasome activity affects the development of cardiac dysfunction differently, depending on the type of heart failure. Studies analyzing the inducible subtype of the proteasome, the immunoproteasome (i20S), demonstrated that the i20S plays a double role in diseased hearts. While i20S subunits are increased in cardiac hypertrophy, atrial fibrillation and partly in myocarditis, the opposite applies to diabetic cardiomyopathy and ischemia/reperfusion injury. In addition, the i20S appears to play a role in autophagy modulation depending on heart failure phenotype. This review summarizes the current literature on the i20S in different heart failure phenotypes, emphasizing the two faces of i20S in injured hearts. A selection of established i20S inhibitors is introduced and signaling pathways linking the i20S to autophagy are highlighted. Mapping the interplay of the i20S and autophagy in different types of heart failure offers potential approaches for developing treatment strategies against heart failure.


Asunto(s)
Autofagia , Insuficiencia Cardíaca , Complejo de la Endopetidasa Proteasomal , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/inmunología , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Fenotipo , Transducción de Señal , Proteolisis , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/genética , Miocarditis/patología , Miocarditis/metabolismo , Miocarditis/inmunología , Miocarditis/genética , Cardiomegalia/patología , Cardiomegalia/metabolismo , Cardiomegalia/genética
14.
Acta Pharmacol Sin ; 45(6): 1175-1188, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38459256

RESUMEN

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 µM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50 µM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD+-SIRT3 axis.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ratones Endogámicos C57BL , Miocitos Cardíacos , NAD , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasa-1 , Sirtuina 3 , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Sirtuina 3/metabolismo , Sirtuina 3/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , NAD/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratones , Ratas , Diabetes Mellitus Experimental/metabolismo , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Dieta Alta en Grasa , Ácido Palmítico/farmacología , Estreptozocina , Ratas Sprague-Dawley , Células Cultivadas
15.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167140, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38548092

RESUMEN

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ratones Endogámicos C57BL , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/tratamiento farmacológico , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Masculino , Ratones , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/tratamiento farmacológico , Estreptozocina , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Fibrosis , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Señalización del Calcio/efectos de los fármacos
16.
BMC Genomics ; 25(1): 312, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38532337

RESUMEN

BACKGROUND: Diabetic cardiomyopathy (DCM) is becoming a very well-known clinical entity and leads to increased heart failure in diabetic patients. Long non-coding RNAs (LncRNAs) play an important role in the pathogenesis of DCM. In the present study, the expression profiles of lncRNAs and mRNAs were illuminated in myocardium from DCM mice, with purpose of exploring probable pathological processes of DCM involved by differentially expressed genes in order to provide a new direction for the future researches of DCM. RESULTS: The results showed that a total of 93 differentially expressed lncRNA transcripts and 881 mRNA transcripts were aberrantly expressed in db/db mice compared with the controls. The top 6 differentially expressed lncRNAs like up-regulated Hmga1b, Gm8909, Gm50252 and down-regulated Msantd4, 4933413J09Rik, Gm41414 have not yet been reported in DCM. The lncRNAs-mRNAs co-expression network analysis showed that LncRNA 2610507I01Rik, 2310015A16Rik, Gm10503, A930015D03Rik and Gm48483 were the most relevant to differentially expressed mRNAs. CONCLUSION: Our results showed that db/db DCM mice exist differentially expressed lncRNAs and mRNAs in hearts. These differentially expressed lncRNAs may be involved in the pathological process of cardiomyocyte apoptosis and fibrosis in DCM.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , ARN Largo no Codificante , Humanos , Ratones , Animales , ARN Largo no Codificante/genética , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Perfilación de la Expresión Génica/métodos , Miocardio/metabolismo , Biología Computacional , ARN Mensajero/genética , Redes Reguladoras de Genes , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología
17.
Front Immunol ; 15: 1348043, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38390337

RESUMEN

Introduction: Diabetes is a debilitating disease that leads to complications like cardiac dysfunction and heart failure. In this study, we investigated the pathophysiology of diabetes-induced cardiac dysfunction in mice with dyslipidemia. We hypothesize diabetes in ApoE knockout (ApoE-/-) mice induces cardiac dysfunction by increasing inflammation and necroptosis. Methods: ApoE-/- mice were divided into experimental groups: Control, Streptozotocin (STZ), STZ + MSC-Exo (mesenchymal stem cell-derived exosomes), and STZ+MEF-Exo (Mouse embryonic fibroblast derived exosomes). At Day 42, we assessed cardiac function, collected blood and heart tissues. Heart tissue samples were analyzed for inflammation, necroptosis, signaling mechanism, hypertrophy and adverse structural remodeling using histology, immunohistochemistry, western blotting, RT-PCR, cytokine array and TF array. Results and Discussion: STZ treated ApoE-/- mice developed diabetes, with significantly (p<0.05) increased blood glucose and body weight loss. These mice developed cardiac dysfunction with significantly (p<0.05) increased left ventricular internal diameter end diastole and end systole, and decreased ejection fraction, and fractional shortening. We found significant (p<0.05) increased expression of inflammatory cytokines TNF- a, IL-6, IL-1a, IL-33 and decreased IL-10 expression. Diabetic mice also exhibited significantly (p<0.05) increased necroptosis marker expression and infiltration of inflammatory monocytes and macrophages. MSC-Exos treated mice showed recovery of diabetes associated pathologies with significantly reduced blood glucose, recovered body weight, increased IL-10 secretion and M2 polarized macrophages in the heart. These mice showed reduced TAK1-pJNK-NFKB inflammation associated expression and improved cardiac function with significantly reduced cardiac hypertrophy and fibrosis compared to diabetic mice. Treatment with MEF-Exos did not play a significant role in attenuating diabetes-induced cardiomyopathy as these treatment mice presented with cardiac dysfunction and underlying pathologies observed in STZ mice. Conclusion: Thus, we conclude that cardiac dysfunction develops in diabetic ApoE-/- mice, arising from inflammation, necroptosis, and adverse tissue remodeling, which is ameliorated by MSC-Exos, a potential therapeutic for diabetes-induced cardiomyopathy.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Exosomas , Cardiopatías , Animales , Ratones , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Glucemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Exosomas/metabolismo , Fibroblastos/patología , Cardiopatías/metabolismo , Inflamación/metabolismo , Interleucina-10/metabolismo , Ratones Noqueados para ApoE , Necroptosis
18.
Acta Biomater ; 176: 367-378, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38244659

RESUMEN

Early detection of myocardial fibrosis in diabetic cardiomyopathy (DCM) has significant clinical implications for diabetes management. In this study, we identified matrix metalloproteinase 2 (MMP2) as a potential biomarker for early fibrosis detection. Based on this finding, we designed a dual-targeting nanoparticle CHP-SPIO-ab MMP2 to specifically target myocardiopathy and MMP2, enabling sensitive fibrosis detection using magnetic resonance imaging (MRI). Our results demonstrate that collagen hyperplasia (early fiber formation) begins to develop in diabetic mice at 12 weeks old, with observable fibrosis occurring at 16 weeks old. Additionally, MMP2 expression significantly up-regulates around collagen starting from 12 weeks of age. T2 MRI analysis revealed significant T2% enhancement in the hearts of 12-week-old diabetic mice following administration of the CHP-SPIO-ab MMP2 probe, indicating noninvasive detection of fiber formation. Furthermore, after fibrosis treatment, a reduction in T2% signal was observed in the hearts of 16-week-old diabetic mice. These findings were supported by Sirius red and Prussian blue staining techniques. Overall, our study presents a promising strategy for early identification of myocardial fibrosis. STATEMENT OF SIGNIFICANCE: Myocardial damage typically exhibits irreversibility, underscoring the paramount importance of early fibrosis diagnosis. However, the clinical used T1 mapping for fibrosis detection still exhibits limitations in terms of sensitivity. Therefore, it is imperative to develop highly sensitive strategies for early cardiac fibrosis detection. Here, we investigated the development of myocardial fibrosis in diabetic mice, and designed a highly sensitive probe that specifically targets cardiomyopathy and high expression of MMP2 for the early diagnosis of fibrosis. The probe enables non-invasive detection of abnormalities through MRI imaging as soon as fiber deposition appear, which can be detected earlier than T1 mapping. This advancement holds great potential for clinical diagnosis of myocardial fibrosis using cardiac magnetic resonance.


Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Compuestos Férricos , Ratones , Animales , Metaloproteinasa 2 de la Matriz/metabolismo , Diabetes Mellitus Experimental/metabolismo , Miocardio/metabolismo , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Fibrosis , Colágeno/metabolismo , Diagnóstico Precoz
19.
Biomed Pharmacother ; 171: 116007, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38171238

RESUMEN

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM). However, the mechanisms underlying DCM-induced cardiac injury remain unclear. Recently, the role of cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling and pyroptosis in DCM has been investigated. Based on our previous results, this study was designed to examine the impact of irisin, mitochondrial ubiquitin ligase (MITOL/MARCH5), and cGAS/STING signaling in DCM-induced cardiac dysfunction and the effect of gasdermin D (GSDMD)-dependent pyroptosis. High-fat diet-induced mice and H9c2 cells were used for cardiac geometry and function or pyroptosis-related biomarker assessment at the end of the experiments. Here, we show that DCM impairs cardiac function by increasing cardiac fibrosis and GSDMD-dependent pyroptosis, including the activation of MITOL and cGAS/STING signaling. Our results confirmed that the protective role of irisin and MITOL was partially offset by the activation of cGAS/STING signaling. We also demonstrated that GSDMD-dependent pyroptosis plays a pivotal role in the pathological process of DCM pathogenesis. Our results indicate that irisin treatment protects against DCM injury, mitochondrial homeostasis, and pyroptosis through MITOL upregulation.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Animales , Ratones , Cardiomiopatías Diabéticas/patología , Fibronectinas , Nucleotidiltransferasas , Piroptosis , Remodelación Ventricular , Ratas
20.
Am J Pathol ; 194(4): 551-561, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38061627

RESUMEN

Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis. At the cellular level, oxidative stress and inflammation in cardiomyocytes are triggered by hyperglycemia. Although males are generally more likely to develop cardiovascular disease than females, diabetic males are less likely to develop diabetic cardiomyopathy than are diabetic females. One reason for these differences may be the higher levels of serum testosterone in males compared with females. Although testosterone appears to protect against cardiomyocyte oxidative stress and exacerbate hypertrophy, its role in inflammation and fibrosis is much less clear. Additional preclinical and clinical studies will be required to delineate testosterone's effect on the diabetic heart.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Hiperglucemia , Hipertensión , Humanos , Masculino , Femenino , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Testosterona/farmacología , Caracteres Sexuales , Cardiomegalia , Estrés Oxidativo , Fibrosis , Inflamación
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