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INTRODUCTION: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED: In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION: We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.
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Cardiomiopatías Diabéticas , Hipoglucemiantes , Humanos , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Animales , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Cardiotónicos/uso terapéutico , Cardiotónicos/farmacología , Quimioterapia Combinada , Fármacos Cardiovasculares/uso terapéutico , Extractos Vegetales/uso terapéutico , Extractos Vegetales/farmacologíaRESUMEN
Cardiomyopathy is one of complications related to diabetes. Stem cell transplantation shows potential in diabetic cardiomyopathy treatment. Epigallocatechin-3-gallate (EGCG) is one of the major components found in green tea. Although stem cell transplantation and green tea EGCG supplementation show therapeutic effects on cardiomyopathy, the detailed cellular mechanisms in stem cell transplantation coupled with EGCG treatment remain unclear. This study investigates whether adipose-derived stem cells (ADSC) pretreated with EGCG show better protective effect on diabetic cardiomyopathy than ADSC without EGCG pretreatment. A cell model indicated that ADSC pretreated with EGCG increased cell functions including colony formation, migration and survival markers. All of these functions are blocked by small interfering C-X-C motif chemokine receptor 4 (siCXCR4) administration. These findings suggest that ADSC pretreatment with EGCG increases cell functions through CXCR4 expression. A diabetic animal model was designed to verify the above findings, including Sham, DM (diabetes mellitus), DM+ADSC (DM rats receiving autologous transplantation of ADSC) and DM+E-ADSC (DM rats receiving EGCG pretreated ADSC). Compared to the Sham, we found that all of pathophysiological signalings were activated in the DM group, including functional changes (decrease in ejection fraction and fractional shortening), structural changes (disarray and fibrosis) and molecular changes (increases in apoptotic, fibrotic, hypertrophic markers and decreases in survival and longevity markers). E-ADSC (DM+E-ADSC) transplantation shows significant improvement in the above pathophysiological signalings greater than ADSC (DM+ADSC). Therefore, ADSC pretreated with EGCG may contribute to clinical applications for diabetic patients with cardiomyopathy.
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Catequina , Cardiomiopatías Diabéticas , Receptores CXCR4 , Té , Animales , Catequina/análogos & derivados , Catequina/farmacología , Catequina/administración & dosificación , Cardiomiopatías Diabéticas/terapia , Té/química , Receptores CXCR4/metabolismo , Masculino , Tejido Adiposo/citología , Ratas Sprague-Dawley , Trasplante Autólogo , Ratas , Trasplante de Células Madre , Modelos Animales de Enfermedad , Células Madre , Regeneración/efectos de los fármacos , Diabetes Mellitus Experimental/terapiaRESUMEN
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.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ratones Endogámicos C57BL , Miocitos Cardíacos , NAD , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasa-1 , Sirtuina 3 , Animales , Masculino , Ratones , Ratas , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Dieta Alta en Grasa , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , NAD/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido Palmítico/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Sirtuina 3/metabolismo , Sirtuina 3/genética , EstreptozocinaRESUMEN
Cardiovascular complications are the leading cause of death in diabetic patients. Among them, diabetic cardiomyopathy (DCM) is a type of specific cardiomyopathy excluding myocardial damage caused by hypertension and coronary heart disease. It is characterized by abnormal metabolism of cardiomyocytes and gradual decline of cardiac function. The clinical manifestations of DCM are impaired diastolic function in early stage and impaired systolic function in late stage. Eventually it developed into heart failure. Mitochondria are the main organelles that provide energy in cardiomyocytes. Mitochondrial dynamics refers to the dynamic process of mitochondrial fusion and fission, which is an important approach for mitochondrial quality control. Mitochondrial dynamics plays a crucial role in maintaining mitochondrial homeostasis and cardiac function. The proteins that regulate mitochondrial fission are mainly Drp1 and its receptors, Fis1, MFF, MiD49 and MiD51. The protein that performs mitochondrial outer membrane fusion is Mfn1/2, and the inner membrane fusion protein is Opa1. This paper reviews recent progress on mitochondrial dynamics in DCM. The main contents are as follows: mitochondrial dynamics imbalance in both type 1 and 2 DCM is manifested as increased fission and inhibited fusion. The molecular mechanism of the former is mainly associated with up-regulated Drp1 and down-regulated Opa1, while the molecular mechanism of the latter is mainly associated with up-regulated Drp1 and down-regulated Mfn1/2. Increased mitochondrial fission and inhibited fusion can lead to mitochondrial dysfunction and promote the development of DCM. The active ingredients of the traditional Chinese medicine such as punicalagin, paeonol and endogenous substance melatonin can improve mitochondrial function and alleviate the symptoms of DCM by inhibiting mitochondrial fission or promoting mitochondrial fusion. This article is helpful to further understand the role and mechanism of mitochondrial dynamics in DCM, and provide new treatment methods and intervention strategies for clinical DCM patients based on mitochondrial dynamics.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Insuficiencia Cardíaca , Humanos , Dinámicas Mitocondriales , Miocardio , Homeostasis , Proteínas de la MembranaRESUMEN
Diabetic cardiomyopathy (DCM) is an important complication resulting in heart failure and death of diabetic patients. However, there is no effective drug for treatments. This study investigated the effect of D-pinitol (DP) on cardiac injury using diabetic mice and glycosylation injury of cardiomyocytes and its molecular mechanisms. We established the streptozotocin-induced SAMR1 and SAMP8 mice and DP (150 mg/kg/day) intragastrically and advanced glycation end-products (AGEs)-induced H9C2 cells. H9C2 cells were transfected with optineurin (OPTN) siRNA and overexpression plasmids. The metabolic disorder indices, cardiac dysfunction, histopathology, immunofluorescence, western blot, and immunoprecipitation were investigated. Our results showed that DP reduced the blood glucose and AGEs, and increased the expression of heart OPTN in diabetic mice and H9C2 cells, thereby inhibiting the endoplasmic reticulum stress (GRP78, CHOP) and glycophagy (STBD1, GABARAPL1), and alleviating the myocardial apoptosis and fibrosis of DCM. The expression of filamin A as an interaction protein of OPTN downregulated by AGEs decreased OPTN abundance. Moreover, OPTN siRNA increased the expression of GRP78, CHOP, STBD1, and GABARAPL1 and inhibited the expression of GAA via GSK3ß phosphorylation and FoxO1. DP may be helpful to treat the onset of DCM. Targeting OPTN with DP could be translated into clinical application in the fighting against DCM.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Inositol/análogos & derivados , Humanos , Ratones , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Chaperón BiP del Retículo Endoplásmico , Miocitos Cardíacos , Estrés del Retículo Endoplásmico , Transducción de Señal , Apoptosis , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/farmacologíaRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM) is the leading cause of diabetic death as the final occurrence of heart failure and arrhythmia. Traditional Chinese medicine is usually used to treat various diseases including diabetes. OBJECTIVE: This study sought to investigate the effects of Traditional Chinese medicine supplementing Qi and activating blood circulation (SAC) in DCM. METHODS: After the construction of the DCM model by streptozotocin (STZ) injection and high glucose/fat diet feeding, rats were administered intragastrically with SAC. Then, cardiac systolic/diastolic function was evaluated by detecting left ventricular systolic pressure (LVSP), maximal rate of left ventricular pressure rise (+LVdp/dtmax), and fall (-LVdp/dtmax), heart rate (HR), left ventricular ejection fraction (EF), LV fractional shortening (FS) and left ventricular end-diastolic pressure (LVEDP). Masson's and TUNEL staining were used to assess fibrosis and cardiomyocyte apoptosis. RESULTS: DCM rats exhibited impaired cardiac systolic/diastolic function manifested by decreasing LVSP, + LVdp/dtmax, -LVdp/dtmax, HR, EF and FS, and increasing LVEDP. Intriguingly, traditional Chinese medicine SAC alleviated the above-mentioned symptoms, indicating a potential role in improving cardiac function. Masson's staining substantiated that SAC antagonized the increased collagen deposition and interstitial fibrosis area and the elevations in protein expression of fibrosisrelated collagen I and fibronectin in heart tissues of DCM rats. Furthermore, TUNEL staining confirmed that traditional Chinese medicine SAC also attenuated cardiomyocyte apoptosis in DCM rats. Mechanically, DCM rats showed the aberrant activation of the TGF-ß/Smad signaling, which was inhibited after SAC. CONCLUSION: SAC may exert cardiac protective efficacy in DCM rats via the TGF-ß/Smad signaling, indicating a new promising therapeutic approach for DCM.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Ratas , Animales , Cardiomiopatías Diabéticas/metabolismo , Medicina Tradicional China , Volumen Sistólico , Qi , Función Ventricular Izquierda , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/uso terapéutico , Fibrosis , Colágeno , Miocardio/metabolismo , Diabetes Mellitus/metabolismoRESUMEN
Diabetic cardiomyopathy (DCM) is a cardiac complication resulting from long-term uncontrolled diabetes, characterized by myocardial fibrosis and abnormal cardiac function. This study aimed at investigating the potential of ginsenoside RG1 (RG1)-induced mesenchymal stem cells (MSCs) in alleviating DCM. A DCM mouse model was constructed, and the effects of RG1-induced MSCs on myocardial function and fibrosis in diabetic mice were evaluated. RG1-induced MSCs were cocultured with high glucose-treated fibroblasts for subsequent functional and mechanism assays. It was discovered that RG1-induced MSCs secrete exosomes that induce macrophage M2 polarization. Mechanistically, exosomes derived from RG1-induced MSCs transferred circNOTCH1 into macrophages, activating the NOTCH signaling pathway. A competing endogenous RNA (ceRNA) regulatory axis consisting of circNOTCH1, miR-495-3p, and NOTCH1 was found to contribute to DCM alleviation.. This study unveiled that exosomal circNOTCH1 secreted by RG1-induced MSCs can alleviate DCM by activating the NOTCH signaling pathway to induce macrophage M2 polarization. This finding may contribute to the development of new therapeutic approaches for DCM.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ginsenósidos , Células Madre Mesenquimatosas , MicroARNs , Ratones , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Macrófagos/metabolismo , MicroARNs/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Based on the theory of traditional Chinese medicine (TCM), diabetic cardiomyopathy (DCM) belongs to the category of "Xiaoke disease" according to the symptoms, and "stasis-heat" is the main pathogenesis of DCM. The Chinese medicine Anemarrhena asphodeloides Bunge (AAB), as a representative of heat-clearing and engendering fluid, is often used clinically in the treatment of DCM. Anemarrhena asphodeloides Bunge total saponins (RATS) are the main bioactive components of AAB, the modern pharmacologic effects of RATS are anti-inflammatory, hypoglycemic, and cardioprotective. However, the potential protective mechanisms of RATS against DCM remain largely undiscovered. AIM OF THE STUDY: The primary goal of this study was to explore the effect of RATS on DCM and its mechanism of action. MATERIALS AND METHODS: Streptozotocin and a high-fat diet were used to induce DCM in rats. UHPLC/Q-TOF-MS was used to determine the chemical components of RATS. The degenerative alterations and apoptotic cells in the heart were assessed by HE staining and TUNEL. Network pharmacology was used to anticipate the probable targets and important pathways of RATS. The alterations in metabolites and main metabolic pathways in heart tissue were discovered using 1 H-NMR metabolomics. Ultimately, immunohistochemistry was used to find critical pathway protein expression. RESULTS: First of all, UHPLC/Q-TOF-MS analysis showed that RATS contained 11 active ingredients. In animal experiments, we found that RATS lowered blood glucose and lipid levels in DCM rats, and alleviated cardiac pathological damage, and decreased cardiomyocyte apoptosis. Furthermore, the study found that RATS effectively reduced inflammatory factor release and the level of oxidative stress. Mechanistically, RATS downregulated the expression levels of PI3K, AKT, HIF-1α, LDHA, and GLUT4 proteins. Additionally, glycolysis was discovered to be a crucial pathway for RATS in the therapy of DCM. CONCLUSIONS: Our findings suggest that the protective effect of RATS on DCM may be attributed to the inhibition of the PI3K/AKT/HIF-1α pathway and the correction of glycolytic metabolism.
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Anemarrhena , Diabetes Mellitus , Cardiomiopatías Diabéticas , Saponinas , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Anemarrhena/química , Saponinas/farmacología , Saponinas/uso terapéutico , Saponinas/química , GlucólisisRESUMEN
BACKGROUND: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. METHODS: db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. RESULTS: rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. CONCLUSIONS: In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Insuficiencia Cardíaca , Animales , Humanos , Ratones , Diabetes Mellitus/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/prevención & control , Insuficiencia Cardíaca/metabolismo , Inflamación/metabolismo , Lipidómica , Lípidos , Miocitos Cardíacos/metabolismo , PPAR gamma/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Volumen Sistólico , Triglicéridos/metabolismo , Función Ventricular IzquierdaRESUMEN
Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Animales , Humanos , Glutamina/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Corazón , Estrés Oxidativo/fisiologíaRESUMEN
This study investigated the effects of trelagliptin and remogliflozin, alone and in combination with alpha lipoic acid (ALA), on cardiac biomarkers in diabetic cardiomyopathy (DCM). We aimed to assess the management of glucotoxicity consequences in streptozotocin-induced diabetic rats by measuring serum levels of pharmacologically active endogenous ligands. Forty-eight male rats were divided into different treatment groups, including negative control, positive control, and four experimental groups. After inducing diabetes, the rats were treated for 28 days, and serum levels of biomarkers associated with oxidative stress (malondialdehyde and thioredoxin-interacting protein), inflammation (nuclear factor NF-kappa-B p105 and lipoprotein-associated phospholipase A2), and myopathy (neprilysin and high selective cardiac troponin T) were measured. Immunohistochemical analysis of heart cells was also performed. The results showed that inducing hyperglycemia increased serum glucose levels and biomarkers associated with DCM. However, all treatment groups exhibited a significant decrease in these biomarkers and an increase in insulin levels compared to the diabetic control group. The groups receiving combination therapy with ALA showed greater improvements in cardiac biomarkers compared to the individual treatments. The immunohistochemical analysis supported these findings by demonstrating a reduction in the percentage area of cathepsin B, a protein involved in DCM pathophysiology. In conclusion, supplementing the base treatments with ALA showed promise in enhancing cardiac biomarkers associated with DCM. The combination of trelagliptin, remogliflozin, and ALA may have additional clinical value in managing DCM by targeting oxidative stress, inflammation, and glucotoxicity. However, further research is needed to validate these findings and explore their potential clinical applications.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ácido Tióctico , Ratas , Masculino , Animales , Ácido Tióctico/farmacología , Ácido Tióctico/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Estreptozocina/farmacología , Estreptozocina/uso terapéutico , Ratas Wistar , Estrés Oxidativo , Cardiomiopatías Diabéticas/metabolismo , Inflamación/complicaciones , Biomarcadores/metabolismoRESUMEN
Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Humanos , Cardiomiopatías Diabéticas/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/metabolismo , Mitocondrias , Miocardio/patología , Miocitos Cardíacos , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
OBJECTIVE: To examine the protective effect of ginsenoside Rb1 (Rb1), the main component of Renshen (), on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia (CIH) and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy (DCM). METHODS: The db/db mice were randomly separated into five groups: normal control group, model group, Rb1 20 mg/kg group, Rb1 40 mg/kg group, and glucagon-like peptide-1 (GLP-1) group. Mice were exposed to air-condition or CIH for 8 weeks, and Rb1 and GLP-1 were administrated before CIH exposure every day. Oral glucose tolerance test (OGTT), intraperitoneal insulin tolerance test (IPITT), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were detected to evaluate glycolipid metabolism. The level of insulin was detected by a mouse enzyme-linked immunosorbent assay (ELISA). Cardiac function was detected by echocardiography, and myocardial pathology was observed by hematoxylin-eosin and Masson staining. The expression of collagen â and collagen â ¢ was detected by immunohistochemistry. Adenosine monophosphate-activated protein kinase (AMPK)/Nrf2/heme oxygenase-1 (HO-1) signaling pathway was detected by Western blot and immunofluorescence. RESULTS: Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes, and inhibit the level of oxidative stress indexes and the expression of collagen â and collagen â ¢. Moreover, Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 expression. CONCLUSION: Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Insulinas , Ratones , Animales , Adenosina Monofosfato , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/genética , Factor 2 Relacionado con NF-E2/genética , Hemo-Oxigenasa 1/genética , Proteínas Quinasas Activadas por AMP/genética , Transducción de Señal , Colágeno Tipo I , ColesterolRESUMEN
Oxidative stress and insulin resistance are two key mechanisms for the development of diabetic cardiomyopathy (DCM, cardiac remodeling and dysfunction). In this review, we discussed how zinc and metallothionein (MT) protect the heart from type 1 or type 2 diabetes (T1D or T2D) through its anti-oxidative function and insulin-mediated PI3K/Akt signaling activation. Both T1D and T2D-induced DCM, shown by cardiac structural remodeling and dysfunction, in wild-type mice, but not in cardiomyocyte-specific overexpressing MT mice. In contrast, mice with global MT gene deletion were more susceptible to the development of DCM. When we used zinc to treat mice with either T1D or T2D, cardiac remodeling and dysfunction were significantly prevented along with increased cardiac MT expression. To support the role of zinc homeostasis in insulin signaling pathways, treatment of diabetic mice with zinc showed the preservation of phosphorylation levels of insulin-mediated glucose metabolism-related Akt2 and GSK-3ß and even rescued cardiac pathogenesis induced by global deletion of Akt2 gene in a MT-dependent manner. These results suggest the protection by zinc from DCM is through both the induction of MT and sensitization of insulin signaling. Combined our own and other works, this review comprehensively summarized the roles of zinc homeostasis in the development and progression of DCM and its therapeutic implications. At the end, we provided pre-clinical and clinical evidence for the preventive and therapeutic potential of zinc supplementation through its anti-oxidative stress and sensitizing insulin signaling actions. Understanding the intricate connections between zinc and DCM provides insights for the future interventional approaches.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Cardiomiopatías Diabéticas , Ratones , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/metabolismo , Zinc/uso terapéutico , Zinc/metabolismo , Insulina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Remodelación Ventricular , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Miocitos Cardíacos/metabolismo , Transducción de Señal , Estrés OxidativoRESUMEN
BACKGROUND: Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. ß-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure. METHODS: C57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism. RESULTS: Ele markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced cardiomyocytes. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation. CONCLUSIONS: The study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Hiperglucemia , Ratones , Animales , FN-kappa B/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ratones Endogámicos C57BL , Hiperglucemia/metabolismo , Miocitos Cardíacos , Inflamación/metabolismoRESUMEN
In diabetic patients, diabetic cardiomyopathy (DCM) is one of the most common causes of death. The inflammatory response is essential in the pathogenesis of DCM. Rhein, an anthraquinone compound, is extracted from the herb rhubarb, demonstrating various biological activities. However, it is unclear whether rhein has an anti-inflammatory effect in treating DCM. In our research, we investigated the anti-inflammatory properties as well as its possible mechanism. According to the findings in vitro, rhein could to exert an anti-inflammatory effect by reducing the production of NO, TNF-α, PGE2, iNOS, and COX-2 in RAW264.7 cells that had been stimulated with advanced glycosylation end products (AGEs). In addition, rhein alleviated H9C2 cells inflammation injury stimulated by AGEs/macrophage conditioned medium (CM). In vivo have depicted that continuous gavage of rhein could improve cardiac function and pathological changes. Moreover, it could inhibit the accumulation of AGEs and infiltration of inflammatory factors inside the heart of rats having DCM. Mechanism study showed rhein could suppress IKKß and IκB phosphorylation via down-regulating TRAF6 expression to inhibit NF-κB pathway in AGEs/CM-induced H9C2 cells. Moreover, the anti-inflammation effect of rhein was realized through down-regulation phosphorylation of JNK MAPK. Furthermore, we found JNK MAPK could crosstalk with NF-κB pathway by regulating IκB phosphorylation without affecting IKKß activity. And hence, the protective mechanism of rhein may involve the inhibiting of the TRAF6-NF/κB pathway, the JNK MAPK pathway, and the crosstalk between the two pathways. These results suggested that rhein may be a promising drug candidate in anti-inflammation and inflammation-related DCM therapy.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Animales , Ratas , Cardiomiopatías Diabéticas/tratamiento farmacológico , FN-kappa B , Quinasa I-kappa B , Factor 6 Asociado a Receptor de TNF , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Proteínas Serina-Treonina Quinasas , Productos Finales de Glicación AvanzadaRESUMEN
Diabetic cardiomyopathy (DCM) is one of the severe complications of diabetes, characterized by structural and functional abnormalities in the hearts of diabetic patients without hypertension, coronary heart disease, or valvular heart disease. DCM can progress to heart failure, which is a significant cause of death in diabetic patients, but currently, there is no effective treatment available. Programmed cell death (PCD) is a genetically regulated form of cell death that includes apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. PCD is essential for tissue homeostasis and normal development of the body. DCM is a complex condition, and abnormalities in the cascade of PCD signaling have been observed in its pathological process, suggesting that targeting PCD could be a potential therapeutic strategy. Studies have shown that natural substances can effectively modulate PCD to intervene in the treatment of DCM, and their use is safe. This review explores the role of different forms of PCD in the pathogenesis of DCM and summarizes the research progress in targeting PCD with natural substances to treat DCM. It can serve as a basis for further research and drug development to provide new treatment strategies for DCM patients.
Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Humanos , Cardiomiopatías Diabéticas/tratamiento farmacológico , Apoptosis , Muerte Celular , Corazón , Resultado del TratamientoRESUMEN
Context: Diabetic cardiomyopathy (DCM) is particularly dangerous in diabetes mellitus (DM). The Shengjie Tongyu decoction (SJTYD) is a well-known, traditional Chinese medicinal formulation that practitioners use to treat myocardial diseases in China; however, its role in DCM remain unclear. Objective: The study intended to investigate: (1) SJTYD's role in the treatment of DCM and its underlying mechanisms, (2) the association of autophagy with DCM, and (3) the involvement of mammalian target of rapamycin (mTOR) signaling in the regulation of DCM. Design: The research team performed an animal study. Setting: The study took place in the Department of Endocrinology in the No. 2 ward-Traditional and Complementary Medicine(TCM) of the China-Japan Friendship Hospital in Beijing, China. Animals: The animals were 60 C57/BL6 mice weighing 200-250 g. Intervention: To determine the role of SJTYD in treating DCM, the research team established a mouse model of DM using streptozotocin (STZ). The team randomly divided the mice into three groups with 20 mice each: (1) a negative control group, which didn't receive injections of STZ or treatment with SJTYD; (2) a model group, the Model group, which received injections of STZ but didn't receive treatment with SJTYD; and (3) an SJTYD group, which received injections of STZ and treatment with SJTYD. Outcome Measures: The research team: (1) conducted a differential analysis to identify the differentially expressed genes; (2) performed deep sequencing of the long noncoding RNAs (lncRNAs) expressed in cardiomyocytes from the control, Model, and SJTYD groups ; (3) performed a bioinformatics analysis; (4) used the ultrasonic and pathological, transmission electron microscopy (TEM) test as well as a Western blot to evaluate cardiac function, myocardial-injury areas, and autophagy in vivo; (5) transfected primary cardiomyocytes treated them with lncRNA H19 and SJTY 3-MA to establish SJTYD subgroups in which the H19 protected against DCM and the 3-MA inhibited autophagy; and (6) carried out immunofluorescence staining and Western blot to test the phosphorylated levels of phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) as well as autophagy levels in vitro. Results: The bioinformatics analysis indicated that SJTYD significantly modulated lncRNA H19 as well as the mTOR pathway. The vevo2100's results indicated the SJTYD reversed the cardiac-dysfunction parameters in DCM. The Masson' staining, TEM, and Western blot demonstrated that the SJTYD could suppress the myocardial-injury areas as well as the numbers of autophagosomes and the expression proteins of autophagy in vivo. The SJTYD promoted the phosphorylated-levels of PI3K, AKT, and mTOR and decreased the levels of autophagy proteins. LC3A-II and Beclin-1; lncRNA H19 amplified the SJTYD's role; and 3-MA reversed those effects, as tested using immunofluorescence and Western blot in primary cardiomyocytes. Conclusions: The SJTYD can protect against diabetic myocardial injury by inhibiting cardiomyocyte autophagy through the activation of lncRNA H19, reactive oxygen species (ROS), and the PI3K/Akt/mTOR signaling pathway. SJTYD may be an effective strategy to ameliorate diabetic myocardial injuries.
Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , ARN Largo no Codificante , Animales , Ratones , Fosfatidilinositol 3-Quinasas , ARN Largo no Codificante/genética , Cardiomiopatías Diabéticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt , Miocitos Cardíacos , Especies Reactivas de Oxígeno , Fosfatidilinositol 3-Quinasa , Serina-Treonina Quinasas TOR , Autofagia , MamíferosRESUMEN
Diabetic cardiomyopathy (DCM) is an important complication leading to the death of patients with diabetes, but there is no effective strategy for clinical treatments. Fufang Zhenzhu Tiaozhi (FTZ) is a patent medicine that is a traditional Chinese medicine compound preparation with comprehensive effects for the prevention and treatment of glycolipid metabolic diseases under the guidance of "modulating liver, starting pivot and cleaning turbidity". FTZ was proposed by Professor Guo Jiao and is used for the clinical treatment of hyperlipidemia. This study was designed to explore the regulatory mechanisms of FTZ on heart lipid metabolism dysfunction and mitochondrial dynamics disorder in mice with DCM, and it provides a theoretical basis for the myocardial protective effect of FTZ in diabetes. In this study, we demonstrated that FTZ protected heart function in DCM mice and downregulated the overexpression of free fatty acids (FFAs) uptake-related proteins cluster of differentiation 36 (CD36), fatty acid binding protein 3 (FABP3) and carnitine palmitoyl transferase 1 (CPT1). Moreover, FTZ treatment showed a regulatory effect on mitochondrial dynamics by inhibiting mitochondrial fission and promoting mitochondrial fusion. We also identified in vitro that FTZ could restore lipid metabolism-related proteins, mitochondrial dynamics-related proteins and mitochondrial energy metabolism in PA-treated cardiomyocytes. Our study indicated that FTZ improves the cardiac function of diabetic mice by attenuating the increase in fasting blood glucose levels, inhibiting the decrease in body weight, alleviating disordered lipid metabolism, and restoring mitochondrial dynamics and myocardial apoptosis in diabetic mouse hearts.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Medicamentos Herbarios Chinos , Enfermedades Metabólicas , Ratones , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Metabolismo de los Lípidos , Dinámicas Mitocondriales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Miocitos Cardíacos , Enfermedades Metabólicas/tratamiento farmacológicoRESUMEN
Diabetic cardiomyopathy (DCM) is a common complication in patients with diabetes, and ultimately leads to heart failure. Endoplasmic reticulum stress (ERS) induced by abnormal glycolipid metabolism is a critical factor that affects the occurrence and development of DCM. Additionally, the upregulation/activation of silent information regulation 2 homolog-1 (SIRT1) has been shown to protect against DCM. Tanshinone II A (Tan IIA), the main active component of Salviae miltiorrhizae radix et rhizome (a valuable Chinese medicine), has protective effects against cardiovascular disease and diabetes. However, its role and mechanisms in diabetes-induced cardiac dysfunction remain unclear. Therefore, we explored whether Tan IIA alleviates ERS-mediated DCM via SIRT1 and elucidated the underlying mechanism. The results suggested that Tan IIA alleviated the pathological changes in the hearts of diabetic mice, ameliorated the cytopathological morphology of cardiomyocytes, reduced the cell death rate, and inhibited the expression of ERS-related proteins and mRNA. The SIRT1 agonist inhibited the activities of glucose-regulated protein 78 (GRP78). Furthermore, the opposite results under the SIRT1 inhibitor. SIRT1 knockdown was induced by siRNA-SIRT1 transfection, and the degree of GRP78 acetylation was increased. Cumulatively, Tan IIA ameliorated DCM by inhibiting ERS and upregulating SIRT1 expression.