RESUMEN
Diabetic cardiomyopathy (DCM), a significant complication of diabetes mellitus, is marked by myocardial structural and functional alterations due to chronic hyperglycemia. Despite its clinical significance, optimal treatment strategies are still elusive. Bariatric surgery via sleeve gastrectomy and Roux-en-Y gastric bypass have shown promise in treating morbid obesity and associated metabolic disorders including improvements in diabetes mellitus and DCM. The present study reviews the molecular mechanisms by which bariatric surgery improves DCM, offering insights into potential therapeutic targets. Future research should further investigate the mechanistic links between bariatric surgery and DCM, to evaluate the benefits and limitations of these surgical interventions for DCM treatment. The present study aims to provide a foundation for more effective DCM therapies, contributing to the advancement of patient care.
Asunto(s)
Cirugía Bariátrica , Cardiomiopatías Diabéticas , Humanos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/terapia , Cardiomiopatías Diabéticas/cirugía , Cirugía Bariátrica/métodos , AnimalesRESUMEN
BACKGROUND: Glucose fluctuations may be involved in the pathophysiological process of cardiomyocyte apoptosis, but the exact mechanism remains elusive. This study focused on exploring the mechanisms related to glucose fluctuation-induced cardiomyocyte apoptosis. METHODS: Diabetic rats established via an injection of streptozotocin were randomized to five groups: the controlled diabetic (CD) group, the uncontrolled diabetic (UD) group, the glucose fluctuated diabetic (GFD) group, the GFD group rats with the injection of 0.9% sodium chloride (NaCl) (GFD + NaCl) and the GFD group rats with the injection of N-acetyl-L-cysteine (NAC) (GFD + NAC). Twelve weeks later, cardiac function and apoptosis related protein expressions were tested. Proteomic analysis was performed to further analyze the differential protein expression pattern of CD and GFD. RESULTS: The left ventricular ejection fraction levels and fractional shortening levels were decreased in the GFD group, compared with those in the CD and UD groups. Positive cells tested by DAB-TUNEL were increased in the GFD group, compared with those in the CD group. The expression of Bcl-2 was decreased, but the expressions of Bax, cleaved caspase-3 and cleaved caspase-9 were increased in response to glucose fluctuations. Compared with CD, there were 527 upregulated and 152 downregulated proteins in GFD group. Txnip was one of the differentially expressed proteins related to oxidative stress response. The Txnip expression was increased in the GFD group, while the Akt phosphorylation level was decreased. The interaction between Txnip and Akt was enhanced when blood glucose fluctuated. Moreover, the application of NAC partially reversed glucose fluctuations-induced cardiomyocyte apoptosis. CONCLUSIONS: Glucose fluctuations lead to cardiomyocyte apoptosis by up-regulating Txnip expression and enhancing Txnip-Akt interaction.
Asunto(s)
Proteínas Reguladoras de la Apoptosis , Apoptosis , Glucemia , Proteínas Portadoras , Diabetes Mellitus Experimental , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Animales , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diabetes Mellitus Experimental/metabolismo , Masculino , Proteínas Portadoras/metabolismo , Glucemia/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Fosforilación , Función Ventricular Izquierda/efectos de los fármacos , Tiorredoxinas/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/etiología , Proteómica , Ratas , Mapas de Interacción de Proteínas , Proteínas de Ciclo CelularRESUMEN
Diabetic cardiomyopathy (DCM) represents one of the typical complications associated with diabetes. It has been described as anomalies in heart function and structure, with consequent high morbidity and mortality. DCM development can be described by two stages; the first is characterized by left ventricular hypertrophy and diastolic dysfunction, and the second by heart failure (HF) with systolic dysfunction. The proposed mechanisms involve cardiac inflammation, advanced glycation end products (AGEs) and angiotensin II. Furthermore, different studies have focused their attention on cardiomyocyte death through the different mechanisms of programmed cell death, such as apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. Exosome release, adipose epicardial tissue and aquaporins affect DCM development. This review will focus on the description of the mechanisms involved in DCM progression and development.
Asunto(s)
Tejido Adiposo , Cardiomiopatías Diabéticas , Exosomas , Fibrosis , Pericardio , Humanos , Exosomas/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Pericardio/metabolismo , Pericardio/patología , Muerte Celular , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Tejido Adiposo EpicárdicoRESUMEN
Myocardial fibrosis can trigger heart failure in diabetic cardiomyopathy (DCM), and irisin, an exercise-induced myokine, may have a beneficial effect on cardiac function. However, the specific molecular mechanism between exercise and irisin in the diabetic heart remains not fully explored. This study aimed to investigate how miR-34a mediates exercise-induced irisin to ameliorate myocardial fibrosis and its underlying mechanisms. Type 2 diabetes mellitus (T2DM) with DCM was induced in adult male rats with high-fat diet and streptozotocin injection. The DCM rats were subjected to swimming (60 min/d) and recombinant irisin (r-irisin, 500 µg/kg/d) interventions for 8 weeks, respectively. Cardiac function, cardiomyocyte structure, myocardial fibrosis and its correlated gene and protein expression were analyzed. Swimming intervention alleviated insulin resistance, myocardial fibrosis, and myocardial hypertrophy, and promoted blood glucose homeostasis in T2DM model rats. This improvement was associated with irisin upregulation and miR-34a downregulation in the myocardium, thus enhancing cardiac function. Similar efficacy was observed via intraperitoneal injection of exogenous recombinant irisin. Inhibition of miR-34a in vivo exhibited an anti-myocardial fibrotic effect by promoting irisin secretion through activating sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5) signal pathway and downregulating myocardial fibrosis markers (collagen I, collagen III, and transforming growth factor-ß1). Therefore, swimming-induced irisin has the potential therapeutic effect on diabetic myocardial fibrosis through activating the miR-34a-mediated SIRT1/PGC-1α/FNDC5 signal pathway.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Fibronectinas , Fibrosis , MicroARNs , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transducción de Señal , Sirtuina 1 , Natación , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Fibronectinas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Ratas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/etiología , Ratas Sprague-Dawley , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
Addressing insulin resistance or hyperinsulinemia might offer a viable treatment approach to stop the onset of diabetic cardiomyopathy, as these conditions independently predispose to the development of the disease, which is initially characterized by diastolic abnormalities. The development of diabetic cardiomyopathy appears to be driven mainly by insulin resistance or impaired insulin signalling and/or hyperinsulinemia. Oxidative stress, hypertrophy, fibrosis, cardiac diastolic dysfunction, and, ultimately, systolic heart failure are the outcomes of these pathophysiological alterations. Melatonin is a ubiquitous indoleamine, a widely distributed compound secreted mainly by the pineal gland, and serves a variety of purposes in almost every living creature. Melatonin is found to play a leading role by improving myocardial cell metabolism, decreasing vascular endothelial cell death, reversing micro-circulation disorders, reducing myocardial fibrosis, decreasing oxidative and endoplasmic reticulum stress, regulating cell autophagy and apoptosis, and enhancing mitochondrial function. This review highlights a relationship between insulin resistance and associated cardiomyopathy. It explores the potential therapeutic strategies offered by the neurohormone melatonin, an important antioxidant that plays a leading role in maintaining glucose homeostasis by influencing the glucose transporters independently and through its receptors. The vast distribution of melatonin receptors in the body, including beta cells of pancreatic islets, asserts the role of this indole molecule in maintaining glucose homeostasis. Melatonin controls the production of GLUT4 and/or the phosphorylation process of the receptor for insulin and its intracellular substrates, activating the insulin-signalling pathway through its G-protein-coupled membrane receptors.
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Cardiomiopatías Diabéticas , Resistencia a la Insulina , Melatonina , Melatonina/metabolismo , Melatonina/uso terapéutico , Melatonina/farmacología , Resistencia a la Insulina/fisiología , Humanos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Animales , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive. RESULTS: We found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown. CONCLUSIONS: Our study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator. Video Abstract.
Asunto(s)
Aminoácidos de Cadena Ramificada , Cardiomiopatías Diabéticas , Factores de Crecimiento de Fibroblastos , Microbioma Gastrointestinal , Hígado , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Ratones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/microbiología , Hígado/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Transducción de Señal , Diabetes Mellitus Tipo 1/microbiología , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , PPAR alfa/metabolismo , Ratones Endogámicos C57BL , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologíaRESUMEN
Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.
Asunto(s)
Cardiomiopatías Diabéticas , Factor 15 de Diferenciación de Crecimiento , Miocitos Cardíacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Ratones , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratones Endogámicos C57BL , Masculino , Diástole/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Inflamación/patología , Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Células THP-1 , Obesidad/metabolismo , Lipopolisacáridos/farmacologíaRESUMEN
Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways.
Asunto(s)
Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Estrés Oxidativo , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/etiología , Animales , Resistencia a la Insulina , Epigénesis Genética , Miocardio/metabolismo , Miocardio/patología , Apoptosis/genéticaRESUMEN
BACKGROUND: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. METHODS: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. FINDINGS: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. INTERPRETATION: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. FUNDING: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).
Asunto(s)
Diabetes Mellitus Experimental , Metabolismo Energético , Estrés Oxidativo , Animales , Ratones , Humanos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Masculino , Ratones Noqueados , Receptores de Hormona Tiroidea/metabolismo , Receptores de Hormona Tiroidea/genética , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Remodelación Atrial , Proteínas de Unión al ADN , Receptores de EsteroidesRESUMEN
Cardiovascular disease including diabetic cardiomyopathy (DbCM) represents the leading cause of death in people with diabetes. DbCM is defined as ventricular dysfunction in the absence of underlying vascular diseases and/or hypertension. The known molecular mediators of DbCM are multifactorial, including but not limited to insulin resistance, altered energy metabolism, lipotoxicity, endothelial dysfunction, oxidative stress, apoptosis, and autophagy. FoxO1, a prominent member of forkhead box O transcription factors, is involved in regulating various cellular processes in different tissues. Altered FoxO1 expression and activity have been associated with cardiovascular diseases in diabetic subjects. Herein we provide an overview of the role of FoxO1 in various molecular mediators related to DbCM, such as altered energy metabolism, lipotoxicity, oxidative stress, and cell death. Furthermore, we provide valuable insights into its therapeutic potential by targeting these perturbations to alleviate cardiomyopathy in settings of type 1 and type 2 diabetes.
Asunto(s)
Cardiomiopatías Diabéticas , Humanos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Animales , Proteína Forkhead Box O1/metabolismo , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMEN
PIWI-interacting RNAs (piRNAs) are involved in the regulation of hypertrophic cardiomyopathy, heart failure and myocardial methylation. However, their functions and the underlying molecular mechanisms in diabetic cardiomyopathy (DCM) have yet to be fully elucidated. In the present study, a pyroptosis-associated piRNA (piR112710) was identified that ameliorates cardiac remodeling through targeting the activation of inflammasomes and mitochondrial dysfunction that are mediated via the thioredoxin-interacting protein (Txnip)/NLRP3 signaling axis. Subsequently, the cardioprotective effects of piR112710 on both the myocardium from db/db mice and cardiomyocytes from neonatal mice that were incubated with a high concentration of glucose combined with palmitate were examined. piR112710 was found to significantly improve cardiac dysfunction in db/db mice, characterized by improved echocardiography, lower levels of fibrosis, attenuated expression levels of inflammatory factors and pyroptosis-associated proteins (namely, Txnip, ASC, NLRP3, caspase-1 and GSDMD-N), and enhanced myocardial mitochondrial respiratory functions. In cultured neonatal mice cardiomyocytes, piR112710 deficiency and high glucose along with palmitate treatment led to significantly upregulated expression levels of pyroptosis associated proteins and collagens, oxidative stress, mitochondrial dysfunction and increased levels of inflammatory factors. Supplementation with piR112710, however, led to a reversal of the aforementioned changes induced by high glucose and palmitate. Mechanistically, the cardioprotective effect of piR112710 appears to be dependent upon effective elimination of reactive oxygen species and inactivation of the Txnip/NLRP3 signaling axis. Taken together, the findings of the present study have revealed that the piRNA-mediated inhibitory mechanism involving the Txnip/NLRP3 axis may participate in the regulation of pyroptosis, which protects against DCM both in vivo and in vitro. piR112710 may therefore be a potential therapeutic target for the reduction of myocardial injury caused by cardiomyocyte pyroptosis in DCM.
Asunto(s)
Proteínas Portadoras , Cardiomiopatías Diabéticas , Miocitos Cardíacos , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/efectos de los fármacos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Proteínas Portadoras/metabolismo , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Masculino , ARN Interferente Pequeño/metabolismo , Ratones Endogámicos C57BL , Tiorredoxinas/metabolismo , Tiorredoxinas/genética , Transducción de Señal/efectos de los fármacos , Inflamasomas/metabolismoRESUMEN
Diabetic cardiomyopathy(DCM) is a chronic complication of diabetes mellitus that leads to cardiac damage in the later stages of the disease, and its pathogenesis is complex, involving metabolic disorders brought about by a variety of aberrant alterations such as endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis, defects in cardiomyocyte Ca~(2+) transporter, and myocardial fibrosis. Currently, there is a lack of specific diagnosis and treatment in the clinic. Autophagy is a highly conserved scavenging mechanism that removes proteins, damaged organelles or foreign contaminants and converts them into energy and amino acids to maintain the stability of the intracellular environment. Inhibition of autophagy can cause harmful metabolites to accumulate in the cell, while over-activation of autophagy can disrupt normal cellular structures and cause cell death. Prolonged high glucose levels disrupt cardiomyocyte autophagy levels and exacerbate the development of DCM. The protective or detrimental effects of autophagy on cells ring true with the traditional Chinese medicine theory of healthy Qi and pathogenic Qi. Autophagy in the physiological state of the removal of intracellular substances and the generation of substances beneficial to the survival of cells is the inhibition of pathogenic Qi to help the performance of healthy Qi, so the organism is healthy. In the early stages of the disease, when autophagy is impaired and incapable of removing waste substances, pathogenic Qi is prevalent; In the later stages of the disease, excessive activation of autophagy can destroy normal cells, leading to a weakening of healthy Qi. Traditional Chinese medicine has the advantage of targeting multiple sites and pathways. Studies in recent years have confirmed that traditional Chinese medicine monomers or formulas can target autophagy, promote the restoration of autophagy levels, maintain mitochondrial and endoplasmic reticulum homeostasis, and reduce oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis in order to prevent and control DCM. This study provides a review of the relationship between autophagy and DCM and the intervention of traditional Chinese medicine in autophagy for the treatment of DCM, with a view to providing new clinical ideas and methods for the treatment of DCM with traditional Chinese medicine.
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Autofagia , Cardiomiopatías Diabéticas , Medicamentos Herbarios Chinos , Medicina Tradicional China , Autofagia/efectos de los fármacos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/fisiopatología , Humanos , Animales , Medicamentos Herbarios Chinos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacosRESUMEN
Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.
Asunto(s)
Canagliflozina , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ratones Endogámicos C57BL , Mitofagia , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Mitofagia/efectos de los fármacos , Masculino , Ratones , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Ratas , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Línea Celular , Transducción de Señal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversosRESUMEN
AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy. METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice. CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.
Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ferroptosis , Miocitos Cardíacos , Biogénesis de Organelos , Receptores Acoplados a Proteínas G , Animales , Masculino , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/genética , Ferroptosis/fisiología , Ferroptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Transducción de SeñalRESUMEN
Diabetic cardiomyopathy (DCM) is one of the serious complications of type 2 diabetes mellitus. Vasant Kusumakar Rasa (VKR) is a Herbo-metallic formulation reported in Ayurveda, an Indian system of medicine. The present work was designed to study the effect of VKR in cardiomyopathy in type 2 diabetic rats. Diabetes was induced by feeding a high-fat diet (HFD) for 2 weeks followed by streptozotocin (STZ) administration (35 mg/kg i.p.). VKR was administered orally at dose of 28 and 56 mg/kg once a day for 16 weeks. The results of the study indicated that VKR treatment significantly improved the glycemic and lipid profile, serum insulin, CK-MB, LDH, and cardiac troponin-I when compared to diabetic control animals. VKR treatment in rats significantly improved the hemodynamic parameters and cardiac tissue levels of TNF-α, IL-1ß, and IL- 6 were also reduced. Antioxidant enzymes such as GSH, SOD, and catalase were improved in all treatment groups. Heart sections stained with H & E and Masson's trichome showed decreased damage to histoarchitecture of the myocardium. Expression of PI3K, Akt, and GLUT4 in the myocardium was upregulated after 16 weeks of VKR treatment. The study data suggested the cardioprotective capability of VKR in the management of diabetic cardiomyopathy in rats.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Estrés Oxidativo , Animales , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Miocardio/patología , Miocardio/metabolismo , Antioxidantes/farmacología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Biomarcadores/sangre , Medicina Ayurvédica , Ratas , Mediadores de Inflamación/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Citocinas/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: Aberrant glucolipid metabolism in the heart is a characteristic factor in diabetic cardiomyopathy (DbCM). Super-enhancers-driven noncoding RNAs (seRNAs) are emerging as powerful regulators in the progression of cardiac diseases. However, the functions of seRNAs in DbCM have not been fully elucidated. METHODS: Super enhancers and their associated seRNAs were screened and identified by H3K27ac ChIP-seq data in the Encyclopedia of DNA Elements (ENCODE) dataset. A dual-luciferase reporter assay was performed to analyze the function of super-enhancers on the transcription of peroxisome proliferator-activated receptor α-related seRNA (PPARα-seRNA). A DbCM mouse model was established using db/db leptin receptor-deficient mice. Adeno-associated virus serotype 9-seRNA (AAV9-seRNA) was injected via the tail vein to evaluate the role of seRNA in DbCM. The underlying mechanism was explored through RNA pull-down, RNA and chromatin immunoprecipitation, and chromatin isolation by RNA purification. RESULTS: PPARα-seRNA was regulated by super-enhancers and its levels were increased in response to high glucose and palmitic acid stimulation in cardiomyocytes. Functionally, PPARα-seRNA overexpression aggravated lipid deposition, reduced glucose uptake, and repressed energy production. In contrast, PPARα-seRNA knockdown ameliorated metabolic disorder in vitro. In vivo, overexpression of PPARα-seRNA exacerbated cardiac metabolic disorder and deteriorated cardiac dysfunction, myocardial fibrosis, and hypertrophy in DbCM. Mechanistically, PPARα-seRNA bound to the histone demethylase KDM4B (Lysine-specific demethylase 4B) and decreased H3K9me3 levels in the promoter region of PPARα, ultimately enhancing its transcription. CONCLUSIONS: Our study revealed the pivotal function of a super-enhancer-driven long noncoding RNA (lncRNA), PPARα-seRNA, in the deterioration of cardiac function and the exacerbation of metabolic abnormalities in diabetic cardiomyopathy, which recruited KDM4B to the promoter region of PPARα and repression of its transcription. This suggests a promising therapeutic strategy for the treatment of DbCM.
Asunto(s)
Cardiomiopatías Diabéticas , Metabolismo de los Lípidos , PPAR alfa , ARN Largo no Codificante , Animales , Masculino , Ratones , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Elementos de Facilitación Genéticos/genética , Glucosa/metabolismo , Metabolismo de los Lípidos/genética , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , PPAR alfa/metabolismo , PPAR alfa/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
OBJECTIVE: To explore the therapeutic mechanism of compound Yuye Decoction against diabetic cardiomyopathy (DCM). METHODS: Drugbank, Gene Cards, OMIM and PharmGKb databases were used to obtain DCM-related targets, and the core targets were identified and functionally annotated by protein-protein interaction network analysis followed by GO and KEGG enrichment analysis. The "Traditional Chinese Medicine-Key Component-Key Target-Key Pathway" network was constructed using Cytoscape 3.9.1, and molecular docking was carried out for the key components and the core targets. In the animal experiment, Wistar rat models of DCM were treated with normal saline or Yuye Decoction by gavage at low (0.29 g/kg) and high (1.15 g/kg) doses for 8 weeks, and the changes in cardiac electrophysiology and histopathology were evaluated. The changes in serum levels of LDH, CK, and CK-MB were examined, and myocardial expressions of PI3K, P-PI3K, Akt, P-AKT, BAX, IL-6, and TNF-α were detected using Western blotting. RESULTS: We identified 61 active compounds in Yuye Decoction with 1057 targets, 3682 DCM-related disease targets, and 551 common targets between them. Enrichment of the core targets suggested that apoptosis, inflammation and the PI3K/Akt pathways were the key signaling pathways for DCM treatment. Molecular docking studies showed that the active components in Yuye Decoction including gold amidohydroxyethyl ester and kaempferol had strong binding activities with AKT1 and PIK3R1. In DCM rat models, treatment with Yuye Decoction significantly alleviated myocardial pathologies, reduced serum levels of LDH, CK and CK-MB, lowered myocardial expressions of BAX, IL-6 and TNF-α, and increased the expressions of P-PI3K and P-AKT. CONCLUSION: The therapeutic effect of compound Yuye Decoction against DCM is mediated by its multiple active components that act on multiple targets and pathways to inhibit cardiomyocyte apoptosis and inflammatory response by regulating the PI3K/Akt signaling pathway.
Asunto(s)
Apoptosis , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Medicamentos Herbarios Chinos , Inflamación , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Wistar , Transducción de Señal , Animales , Ratas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Inflamación/metabolismo , Miocardio/metabolismo , Miocardio/patología , Masculino , Interleucina-6/metabolismoRESUMEN
In recent years, the incidence of diabetes has been increasing rapidly, posing a serious threat to human health. Diabetic cardiomyopathy (DCM) is characterized by cardiomyocyte hypertrophy, myocardial fibrosis, apoptosis, ventricular remodeling, and cardiac dysfunction in individuals with diabetes, ultimately leading to heart failure and mortality. However, the underlying mechanisms contributing to DCM remain incompletely understood. With advancements in molecular biology technology, accumulating evidence has shown that numerous non-coding RNAs (ncRNAs) crucial roles in the development and progression of DCM. This review aims to summarize recent studies on the involvement of three types of ncRNAs (micro RNA, long ncRNA and circular RNA) in the pathophysiology of DCM, with the goal of providing innovative strategies for the prevention and treatment of DCM.
Asunto(s)
Cardiomiopatías Diabéticas , ARN Circular , ARN Largo no Codificante , Humanos , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Animales , ARN Circular/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Regulación de la Expresión Génica , ARN no Traducido/genética , ARN no Traducido/metabolismo , Transducción de Señal , Miocardio/patología , Miocardio/metabolismoAsunto(s)
Arginina , Cardiomiopatías Diabéticas , Suplementos Dietéticos , Mitocondrias Cardíacas , Humanos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/tratamiento farmacológico , Arginina/administración & dosificación , Arginina/uso terapéutico , Animales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/patologíaRESUMEN
Nimbolide has been demonstrated to possess protective properties against gestational diabetes mellitus and diabetic retinopathy. However, the role and molecular mechanism of nimbolide in diabetic cardiomyopathy (DCM) remain unknown. Diabetes was induced in rats via a single injection of streptozotocin (STZ) and then the diabetic rats were administered nimbolide (5â¯mg/kg and 20â¯mg/kg) or dimethyl sulfoxide daily for 12 weeks. H9c2 cardiomyocytes were exposed to high glucose (25â¯mM glucose) to mimic DCM in vitro. The protective effects of nimbolide against DCM were evaluated in vivo and in vitro. The potential molecular mechanism of nimbolide in DCM was further explored. We found that nimbolide dose-dependently decreased blood glucose and improved body weight of diabetic rats. Additionally, nimbolide dose-dependently improved cardiac function, alleviated myocardial injury/fibrosis, and inhibited endoplasmic reticulum (ER) stress and apoptosis in diabetic rats. Moreover, nimbolide dose-dependently improved mitochondrial function and activated the Akt/mTOR signaling. We consistently demonstrated the cardioprotective effects of nimbolide in an in vitro model of DCM. The involvement of ER stress and mitochondrial pathways were further confirmed by using inhibitors of ER stress and mitochondrial division. By applying a specific Akt inhibitor SC66, the cardioprotective effects of nimbolide were partially blocked. Our study indicated that nimbolide alleviated DCM by activating Akt/mTOR pathway. Nimbolide may be a novel therapeutic agent for DCM treatment.