RESUMEN
BACKGROUND: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy. METHODS AND RESULTS: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998). CONCLUSIONS: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.
Asunto(s)
Cardiomiopatías Diabéticas , Fenofibrato , Insuficiencia Cardíaca , Hipolipemiantes , Obesidad , Fenofibrato/uso terapéutico , Fenofibrato/farmacología , Animales , Obesidad/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Masculino , República de Corea/epidemiología , Humanos , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Ratones Endogámicos C57BL , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , PPAR alfa/agonistas , PPAR alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factores de Tiempo , Bases de Datos Factuales , Transducción de Señal/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Femenino , Hospitalización , Persona de Mediana Edad , Anciano , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/sangre , Factores de Riesgo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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
Diabetes is a major risk factor for cardiovascular diseases, and myocardial damage caused by hyperglycemia is the main cause of heart failure. However, there is still a lack of systematic understanding of myocardial damage caused by diabetes. At present, we believe that the cellular inflammatory damage caused by hyperglycemia is one of the causes of diabetic cardiomyopathy. Pyroptosis, as a proinflammatory form of cell death, is closely related to the occurrence and development of diabetic cardiomyopathy. Therefore, this paper focuses on the important role of inflammation in the occurrence and development of diabetic cardiomyopathy. From the perspective of pyroptosis, we summarize the pyroptosis of different types of cells in diabetic cardiomyopathy and its related signaling pathways. It also summarizes the treatment of diabetic cardiomyopathy, hoping to provide methods for the prevention and treatment of diabetic cardiomyopathy by inhibiting pyroptosis.
Asunto(s)
Cardiomiopatías Diabéticas , Piroptosis , Piroptosis/efectos de los fármacos , Piroptosis/fisiología , Cardiomiopatías Diabéticas/terapia , Cardiomiopatías Diabéticas/prevención & control , Humanos , Animales , Transducción de Señal/efectos de los fármacos , Miocardio/patología , Miocardio/metabolismoRESUMEN
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 SeñalAsunto(s)
Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Nefropatías Diabéticas , Agonistas Receptor de Péptidos Similares al Glucagón , Hipoglucemiantes , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/prevención & control , Aprobación de Drogas , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Agonistas Receptor de Péptidos Similares al Glucagón/administración & dosificación , Agonistas Receptor de Péptidos Similares al Glucagón/efectos adversos , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/prevención & control , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/mortalidad , Cardiomiopatías Diabéticas/prevención & control , Inyecciones Subcutáneas , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(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.
Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Estrés del Retículo Endoplásmico , Limoninas , Mitocondrias , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Limoninas/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Sprague-Dawley , Línea Celular , Apoptosis/efectos de los fármacos , Cardiotónicos/farmacologíaRESUMEN
Diabetic cardiomyopathy may result from the overproduction of ROS, TRPM2 and TRPV2. Moreover, the therapeutic role of ginger, omega-3 fatty acids, and their combinations on the expression of TRPM2 and TRPV2 and their relationship with apoptosis, inflammation, and oxidative damage in heart tissue of rats with type 2 diabetes have not yet been determined. Therefore, this study aimed to investigate the therapeutic effects of ginger and omega-3 fatty acids on diabetic cardiomyopathy by evaluating the cardiac gene expression of TRPM2 and TRPV2, oxidative damage, inflammation, and apoptosis in male rats. Ninety adult male Wistar rats were equally divided into nine control, diabetes, and treated diabetes groups. Ginger extract (100 mg/kg) and omega-3 fatty acids (50, 100, and 150 mg/kg) were orally administrated in diabetic rats for 6 weeks. Type 2 diabetes was induced by feeding a high-fat diet and a single dose of STZ (40 mg/kg). Glucose, cardiac troponin I (cTnI), lipid profile, insulin in serum, and TNF-alpha IL-6, SOD, MDA, and CAT in the left ventricle of the heart were measured. The cardiac expression of TRPM2, TRPV2, NF-kappaB, Bcl2, Bax, Cas-3, and Nrf-2 genes was also measured in the left ventricle of the heart. An electrocardiogram (ECG) was continuously recorded to monitor arrhythmia at the end of the course. The serum levels of cTnI, glucose, insulin, and lipid profile, and the cardiac levels of MDA, IL-6, and TNF-alpha increased in the diabetic group compared to the control group (p<0.05). Moreover, the cardiac levels of SOD and CAT decreased in the diabetic group compared to the control group (p<0.05). The cardiac expression of TRPM2, TRPV2, NF-kappaB, Bax, and Cas-3 increased and Bcl2 and Nrf-2 expression decreased in the diabetic group compared to the control group (p<0.05). However, simultaneous and separate treatment with ginger extract and omega-3 fatty acids (50, 100, and 150 mg/kg) could significantly moderate these changes (p<0.05). The results also showed that the simultaneous treatment of ginger extract and different doses of omega-3 fatty acids have improved therapeutic effects than their individual treatments (p<0.05). It can be concluded that ginger and omega-3 fatty acids showed protective effects against diabetic cardiomyopathy by inhibiting inflammation, apoptosis and oxidative damage of the heart and reducing blood glucose and cardiac expression of TRPM2 and TRPV2. Combining ginger and omega-3 in the diet may provide a natural approach to reducing the risk or progression of diabetic cardiomyopathy while preserving heart structure and function.
Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ácidos Grasos Omega-3 , Extractos Vegetales , Ratas Wistar , Zingiber officinale , Animales , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/administración & dosificación , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/uso terapéutico , Zingiber officinale/química , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Ratas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Suplementos Dietéticos , Estrés Oxidativo/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/genéticaRESUMEN
The incidence of cardiovascular disorders is continuously rising, and there are no effective drugs to treat diabetes-associated heart failure. Thus, there is an urgent need to explore alternate approaches, including natural plant extracts, which have been successfully exploited for therapeutic purposes. The current study aimed to explore the cardioprotective potential of Phoenix dactylifera (PD) extract in experimental diabetic cardiomyopathy (DCM). Following in vitro phytochemical analyses, Wistar albino rats (N = 16, male; age 2-3 weeks) were fed with a high-fat or standard diet prior to injection of streptozotocin (35 mg/kg i.p.) after 2 months and separation into the following four treatment groups: healthy control, DCM control, DCM metformin (200 mg/kg/day, as the reference control), and DCM PD treatment (5 mg/kg/day). After 25 days, glucolipid and myocardial blood and serum markers were assessed along with histopathology and gene expression of both heart and pancreatic tissues. The PD treatment improved glucolipid balance (FBG 110 ± 5.5 mg/dL; insulin 17 ± 3.4 ng/mL; total cholesterol 75 ± 8.5 mg/dL) and oxidative stress (TOS 50 ± 7.8 H2O2equiv./L) in the DCM rats, which was associated with preserved structural integrity of both the pancreas and heart compared to the DCM control (FBG 301 ± 10 mg/dL; insulin 27 ± 3.4 ng/mL; total cholesterol 126 ± 10 mg/dL; TOS 165 ± 12 H2O2equiv./L). Gene expression analyses revealed that PD treatment upregulated the expression of insulin signaling genes in pancreatic tissue (INS-I 1.69 ± 0.02; INS-II 1.3 ± 0.02) and downregulated profibrotic gene expression in ventricular tissue (TGF-ß 1.49 ± 0.04) compared to the DCM control (INS-I 0.6 ± 0.02; INS-II 0.49 ± 0.03; TGF-ß 5.7 ± 0.34). Taken together, these data indicate that Phoenix dactylifera may offer cardioprotection in DCM by regulating glucolipid balance and metabolic signaling.
Asunto(s)
Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Metabolismo de los Lípidos , Phoeniceae , Extractos Vegetales , Ratas Wistar , Animales , Phoeniceae/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Masculino , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/prevención & control , Ratas , Metabolismo de los Lípidos/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Metanol/química , Estrés Oxidativo/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.
Asunto(s)
Compuestos de Bencidrilo , Biomarcadores , Diabetes Mellitus Tipo 2 , Glucósidos , Mediadores de Inflamación , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Femenino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Mediadores de Inflamación/sangre , Biomarcadores/sangre , Factores de Tiempo , Antiinflamatorios/uso terapéutico , Fibrosis , Inflamación/tratamiento farmacológico , Inflamación/sangre , Inflamación/diagnóstico , Método Doble Ciego , Miocardio/patología , Miocardio/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/sangreRESUMEN
AIMS/INTRODUCTION: Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model. MATERIALS AND METHODS: Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 µL phosphate-buffered saline; the small-dose Treg group, administered 105 Tregs; the large-dose Treg group, administered 106 Tregs; and the PC group, administered 100 µg anti-CD25 specific antibody (PC61) and 106 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out. RESULTS: Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM. CONCLUSIONS: Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.
Asunto(s)
Cardiomiopatías Diabéticas , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/inmunología , Masculino , Ratones , Estrés Oxidativo , Apoptosis , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/inmunología , Modelos Animales de Enfermedad , Transducción de SeñalRESUMEN
In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis.
Asunto(s)
Ácido Araquidónico , Ferroptosis , Isquemia Miocárdica , Humanos , Ácido Araquidónico/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/prevención & control , Isquemia Miocárdica/tratamiento farmacológico , Animales , Ferroptosis/efectos de los fármacos , Medición de Riesgo , Comorbilidad , Factores de Riesgo , Miocardio/metabolismo , Miocardio/patología , Transducción de Señal , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/epidemiología , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacosRESUMEN
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 alfaRESUMEN
Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent non-communicable disease. Hyperglycemia in DM is a known risk factor for cardiovascular diseases (CVDs), which substantially impact global mortality rates. This review examines the potential effects of naringin, a citrus flavonoid, on both DM and its associated cardiovascular complications, including conditions like diabetic cardiomyopathy. The safety profile of naringin is summarized based on various pre-clinical studies. The data for this review was gathered from diverse electronic databases, including Medline, PubMed, ScienceDirect, SpringerLink, Google Scholar, and Emerald Insight. Multiple pre-clinical studies have demonstrated that naringin exerts hypoglycemic and cardioprotective effects by targeting various vascular mechanisms. Specifically, research indicates that naringin down-regulates the renin-angiotensin and oxidative stress systems while concurrently upregulating ß-cell and immune system functions. Clinical trial outcomes also support the therapeutic potential of naringin in managing hyperglycemic states and associated cardiovascular issues. Moreover, toxicity studies have confirmed the safety of naringin in animal models, suggesting its potential for safe administration in humans. In conclusion, naringin emerges as a promising natural candidate for both antidiabetic and cardioprotective purposes, offering potential improvements in health outcomes. While naringin presents a new avenue for therapies targeting DM and CVDs, additional controlled and long-term clinical trials are necessary to validate its efficacy and safety for human use.
Asunto(s)
Cardiotónicos , Flavanonas , Hipoglucemiantes , Flavanonas/farmacología , Flavanonas/uso terapéutico , Humanos , Animales , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Estrés Oxidativo/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
Diabetes mellitus (DM) is a collection of metabolic disorder that is characterized by chronic hyperglycemia. Recent studies have demonstrated the crucial involvement of oxidative stress (OS) and inflammatory reactions in the development of DM. Curcumin (CUR), a natural compound derived from turmeric, exerts beneficial effects on diabetes mellitus through its interaction with the nuclear factor kappa B (NF-κB) pathway. Research indicates that CUR targets inflammatory mediators in diabetes, including tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), by modulating the NF-κB signaling pathway. By reducing the expression of these inflammatory factors, CUR demonstrates protective effects in DM by improving pancreatic ß-cells function, normalizing inflammatory cytokines, reducing OS and enhancing insulin sensitivity. The findings reveal that CUR administration effectively lowered blood glucose elevation, reinstated diminished serum insulin levels, and enhanced body weight in Streptozotocin -induced diabetic rats. CUR exerts its beneficial effects in management of diabetic complications through regulation of signaling pathways, such as calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII), peroxisome proliferator-activated receptor gamma (PPAR-γ), NF-κB, and transforming growth factor ß1 (TGFB1). Moreover, CUR reversed the heightened expression of inflammatory cytokines (TNF-α, Interleukin-1 beta (IL-1ß), IL-6) and chemokines like MCP-1 in diabetic specimens, vindicating its anti-inflammatory potency in counteracting hyperglycemia-induced alterations. CUR diminishes OS, avert structural kidney damage linked to diabetic nephropathy, and suppress NF-κB activity. Furthermore, CUR exhibited a protective effect against diabetic cardiomyopathy, lung injury, and diabetic gastroparesis. Conclusively, the study posits that CUR could potentially offer therapeutic benefits in relieving diabetic complications through its influence on the NF-κB pathway.
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Curcumina , Diabetes Mellitus Experimental , Diabetes Mellitus , FN-kappa B , Estrés Oxidativo , FN-kappa B/metabolismo , Curcumina/química , Curcumina/farmacología , Curcumina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Insulina/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Glucemia/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Ratas , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Quimiocina CCL2/metabolismo , Cardiomiopatías Diabéticas/prevención & control , Gastroparesia/prevención & control , Neuropatías Diabéticas/prevención & control , RatonesRESUMEN
A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.
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Proteínas Quinasas Activadas por AMP , Apoptosis , Autofagia , Diabetes Mellitus Experimental , Quercetina , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Quercetina/farmacología , Transducción de Señal/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Ratas Sprague-Dawley , Ratas , Modelos Animales de Enfermedad , Miocardio/metabolismo , Miocardio/patología , Estreptozocina , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/prevención & control , Fitoterapia , Beclina-1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicacionesRESUMEN
BACKGROUND: As a common complication of diabetes, diabetic cardiomyopathy (DCM) often leads to further damage to the heart muscle. Curcumin has been proven to have a variety of cardioprotective effects, however, the protective effect against DCM has not been systematically reviewed. PURPOSE: In this study, we aimed to analyze the preclinical (animal model) evidence of curcumin's therapeutic effects in DCM. METHODS: Eight databases and two registry systems were searched from the time of library construction to 1 November 2023. We performed rigorous data extraction and quality assessment. The included studies' methodological quality was appraised using the SYRCLE RoB tool, statistical analyses were carried out using RevMan 5.4 software, and Funnel plots and Egger's test were performed using Stata 17.0 software to assess publication bias. RESULTS: This study included 32 trials with a total of 681 animals. Meta-analysis showed that curcumin significantly improved cardiac function indices (LVEF, LVFS, and LVSd) (p < 0.01), decreased markers of myocardial injury, HW/BW ratio, and randomized blood glucose compared to the control group, in addition to showing beneficial effects on mechanistic indices of myocardial oxidation, inflammation, apoptosis, and autophagy (p < 0.05). CONCLUSIONS: Curcumin may exert cardioprotective effects in DCM through its antioxidant, anti-inflammatory, autophagy-enhancing, and anti-apoptotic effects. Its protective effect is proportional to the dose, and the efficacy may be further increased at a concentration of more than 200 mg/kg, and further validation is needed.
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Cardiotónicos , Curcumina , Cardiomiopatías Diabéticas , Curcumina/farmacología , Curcumina/uso terapéutico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Animales , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Apoptosis/efectos de los fármacosRESUMEN
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.
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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/genéticaRESUMEN
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.