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1.
Life Sci ; 243: 117251, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31904365

RESUMO

AIMS: Heat shock protein 27 regulates homeostasis of skeletal and cardiac muscle proteins in various stressful states including diabetes and exercise. Aerobic exercise can inhibit or ameliorate cardiac structural abnormality and dysfunction in diabetic cardiomyopathy. The aim of this study was to evaluate the role of HSP27 in aerobic exercise improving cardiac diastolic dysfunction in type 2 diabetic rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into the following groups: control, control + aerobic exercise, diabetic, and diabetic + aerobic exercise. Diabetes was induced by feeding with a high-fat high-sugar diet for 7-weeks followed by a single intraperitoneal injection of streptozotocin (30 mg/kg) in male rats. Moderate aerobic exercise training was performed on a treadmill for 8 weeks after induction of diabetes. KEY FINDINGS: Aerobic exercise increased left ventricular end-diastolic internal diameter, left ventricular end-diastolic volume, myocardial HSP27 protein expression, HSP27-S82 phosphorylation levels, pHSP27-titin binding and improved cardiac muscle fibre alignment in diabetic rats. SIGNIFICANCE: Our study indicates that moderate aerobic exercise increases HSP27 activation, improves cardiomyocyte fibre alignment and restores cardiac diastolic function.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Condicionamento Físico Animal , Animais , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Testes de Função Cardíaca , Humanos , Lipídeos/sangue , Masculino , Miocárdio/metabolismo , Fosforilação , Ratos Sprague-Dawley , Estreptozocina/administração & dosagem
2.
J Biochem Mol Toxicol ; 34(2): e22423, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729781

RESUMO

MicroRNAs are endogenous small noncoding RNAs that posttranscriptionally regulate the expression of target genes and play crucial roles in diverse physiopathologic processes. In the current study, we examined the microRNA (miRNA) expression profile of high-glucose-treated neonatal rat cardiomyocytes and the potential mechanisms. Differentially expressed miRNAs were analyzed by a miRNA microarray and validated by a quantitative real-time polymerase chain reaction in high-glucose-treated rat cardiomyocytes. Based on the results of our previous study and the bioinformatics prediction, we identified miR-195-5p/SGK1/Nedd4-2/hERG as the top-ranked signal pathway in diabetes cell model in vitro. In summary, our present study provides novel insights into the regulatory mechanism of miR-195-5p/SGK1/Nedd4-2/hERG in rat cardiomyocytes under high-glucose stress, which may provide a novel idea for the development of diagnostic and therapeutic strategies for diabetic cardiomyopathy in the future.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Glucose/farmacologia , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Transcriptoma , Regiões 3' não Traduzidas/genética , Animais , Sítios de Ligação , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Imediatamente Precoces/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Transfecção
3.
J Agric Food Chem ; 67(51): 14074-14085, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31793297

RESUMO

Ginsenoside-Rb1 (Rb1), a major active component of ginseng, has many benefits for cardiovascular disease and diabetes mellitus (DM), but the effect and mechanism on diabetic cardiomyopathy are not clear. In the present study, we found that Rb1-feeding significantly improved cardiac dysfunction and abnormal cardiomyocytes calcium signaling caused by diabetes. This improved calcium signaling was because Rb1 reduced Ca2+ leakage caused by overactivated ryanodine receptor 2 (RyR2) and increased Ca2+ uptake by sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA 2a). Furthermore, we found that Rb1 not only enhanced energy metabolism like metformin and eliminated O-GlcNAcylation of calcium handling proteins to regulate calcium signaling but also directly inhibited RyR2 activity to regulate calcium signaling. The present study indicated that as a health supplement or drug, Rb1 was a relatively effective auxiliary therapeutic substance for diabetic cardiomyopathy.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatias Diabéticas/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Proteínas/metabolismo , Acilação , Animais , Cálcio/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
4.
Basic Res Cardiol ; 114(5): 35, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388770

RESUMO

We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1ß, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1ß, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1ß, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inflamassomos/efeitos dos fármacos , Linagliptina/farmacologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Dipeptidil Peptidase 4 , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Curr Protein Pept Sci ; 20(10): 976-983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31362653

RESUMO

Diabetes mellitus (DM) has become an increasingly common disease with high disability and mortality rates. Diabetes complications are the main cause of diabetes death and about 50% of diabetic patients died from heart disease in developed countries reported by World Health Organization. Diabetic cardiomyopathy (DCM) has been considered as a high incidence and serious complication of DM and plays a key role in the incidence and development of diabetes related heart failure. Metabolism dysregulation is regarded as an important and earlier factor occurred in the pathogenesis of DCM. Insulin resistance, oxidative stress, inflammation and mitochondrial dysfunction also contribute to the development of DCM. Farnesoid X Receptor (FXR) is a member of nuclear receptor superfamily, and plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation. FXR is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists such as obeticholic acid. BAs are the main active ingredients of many natural products and traditional medicines, especially bile or gallstones in animals, such as calculus bovis. Due to the regulatory effect of FXR on glucose and lipid metabolism, oxidative stress and inflammation, the treatment of BAs and FXR agonists for metabolic syndrome and DCM have gained more attention. This review will focus on the pathogenesis of diabetic cardiomyopathy and the regulatory effect of BAs and FXR on DCM.


Assuntos
Ácidos e Sais Biliares/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Biomarcadores/metabolismo , Glucose/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos
6.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269778

RESUMO

The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15-20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described.


Assuntos
Cardiomiopatias Diabéticas/patologia , Miocárdio/patologia , Animais , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada/genética , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Inflamação/complicações , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo
7.
Mol Med Rep ; 20(3): 2051-2062, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322242

RESUMO

The incidence of diabetes mellitus has become a major public health concern due to lifestyle alterations. Moreover, the complications associated with diabetes mellitus deeply influence the quality of life of patients. Diabetic cardiomyopathy (DC) is a type of diabetes mellitus complication characterized by functional and structural damage in the myocardium but not accompanied by coronary arterial disease. Currently, diagnosing and preventing DC is still a challenge for physicians due to its atypical symptoms. For this reason, it is necessary to summarize the current knowledge on DC, especially in regards to the underlying molecular mechanisms toward the goal of developing useful diagnostic approaches and effective drugs based on these mechanisms. There exist several review articles which have focused on these points, but there still remains a lot to learn from published studies. In this review, the features, diagnosis and molecular mechanisms of DC are reviewed. Furthermore, potential therapeutic and prophylactic drugs are discussed.


Assuntos
Cardiomiopatias Diabéticas/diagnóstico , Cardiomiopatias Diabéticas/patologia , Miocárdio/patologia , Animais , Biomarcadores/análise , Cateterismo Cardíaco , Angiografia Coronária , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Ecocardiografia , Humanos , Imagem por Ressonância Magnética , Terapia de Alvo Molecular , Miocárdio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Diabetes Metab Syndr ; 13(2): 1523-1528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336516

RESUMO

AIMS: The aim was to see the frequency of CAN in type 2 diabetes mellitus patients with peripheral neuropathy, and its association with peripheral nerve conduction abnormalities. METHODS: A cross-sectional study at BIRDEM was conducted in 62 patients with type 2 diabetes mellitus having electrophysiologically diagnosed peripheral neuropathy. CAN was detected by four clinical tests - heart rate response to deep breathing and valsalva maneuver, blood pressure response to standing and sustained handgrip. RESULT: The study showed that all patients had CAN - 14.52% had early, 26.67% had definitive and 59.68% had severe CAN. Patients with severe CAN had significantly reduced nerve conduction velocity and amplitude of peripheral nerves (sural 4.36 ±â€¯12.77 vs 9.65 ±â€¯17.77 m/s, p = 0.009; 2.23 ±â€¯1.89 vs 3.01 ±â€¯2.76 mV, p = 0.001; peroneal 7 ±â€¯4.23 vs 8.53 ±â€¯5.99 mV, p = 0.047; tibial 0.008 ±â€¯0.03 vs 0.026 ±â€¯0.05 mV, p = 0.009) and higher serum triglyceride levels (221.17 ±â€¯120.61 vs 197.76 ±â€¯68.43 mg/dl, p = 0.033). CONCLUSION: Diabetic patients with peripheral neuropathy have CAN, the severity of which increases with worsening neuropathy.


Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Adolescente , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/metabolismo , Doenças do Sistema Nervoso Autônomo/patologia , Biomarcadores/análise , Glicemia/análise , Estudos Transversais , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
9.
Gene ; 715: 143995, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31336140

RESUMO

Diabetic cardiomyopathy (DCM) refers to the myocardial dysfunction in the absence of coronary artery disease and hypertension. Recently, the role of microRNAs (miRs) in gene expression regulation has attracted much more attention. Studies have shown that the PI3K/Akt signaling pathway is involved in the growth, metabolism and apoptosis of myocardial cells. Therefore, this study aimed to explore the regulatory role of miR-203 in myocardial fibrosis in mice with DCM via involvement of the PI3K/Akt signaling pathway. Firstly, mouse model of diabetes mellitus (DM) was established and injected with agomir, antagomir or IGF-1 (PI3K/Akt signaling pathway activator) for investigating the role of miR-203 in PIK3CA and the PI3K/Akt signaling pathway. PIK3CA was identified as a target gene of miR-203, and overexpressed miR-203 inhibited the activation of PI3K/Akt signaling pathway. The obtained results indicated that up-regulation of miR-203 reduced myocardial hypertrophy, myocardial fibrosis, myocardial apoptosis, and levels of PIK3CA, PI3K, Akt, CoI I, CoI III, ANP, MDA and ROS in the myocardial tissues, by which DM-induced cardiac dysfunction and pathological changes could be ameliorated. Collectively, our present study highlighted that overexpression of miR-203 may function as a cardioprotective regulator in DCM by targeting PIK3CA via inactivation of PI3K/Akt signaling pathway.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/patologia , Fibrose , Camundongos , Miocárdio/patologia
10.
Int J Mol Sci ; 20(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212580

RESUMO

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Insulina/metabolismo , Animais , Cardiomiopatias Diabéticas/genética , Humanos , Resistência à Insulina/fisiologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
11.
Mol Med Rep ; 20(2): 1093-1102, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173208

RESUMO

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and myocardial fibrosis is its major pathological feature. Calcium­sensing receptor (CaSR) is a G protein­coupled receptor and participates in the regulation of calcium homeostasis; it is implicated in a range of diseases, including myocardial ischemia/reperfusion injury, myocardial infarction and pulmonary hypertension. However, whether CaSR is associated with myocardial fibrosis in DCM has remained elusive. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts (CFs) were used to observe changes in CaSR to assess its potential as an indicator of myocardial fibrosis. The in vivo experiments revealed that in the T1D and CaSR agonist (R568) groups, evident collagen (Col)­I and ­III deposition was present after 12 weeks. Furthermore, the in vitro experiment indicated that the levels of transforming growth factor (TGF)­ß1, phosphorylated (p­) protein kinase C, p­p38, p­Smad2, TßRI, TßRII, along with the intracellular Ca2+ levels and the content of TGF­ß1 in the culture medium were significantly increased in a high­glucose (HG) group and an R568­treated group. Treatment with the CaSR inhibitor Calhex231 significantly inhibited the abovementioned changes. Collectively, the results indicated that the increase of CaSR expression in CFs may induce intracellular Ca2+ increases and the activation of TGF­ß1/Smads, and enhance the proliferation of CFs, along with the excessive deposition of Col, resulting in myocardial fibrosis. The present results indicate an important novel mechanism for HG­induced myocardial fibrosis and suggest that CaSR may be a promising potential therapeutic target for DCM.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Fibroblastos/metabolismo , Fibrose/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Transdução de Sinais , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Fibroblastos/fisiologia , Fibrose/complicações , Fibrose/etiologia , Coração/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Wistar , Proteínas Smad Reguladas por Receptor/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Biol Pharm Bull ; 42(8): 1337-1344, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31167987

RESUMO

Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and features myocardial fibrosis as its main pathological feature. Calcium sensing receptor (CaSR) is a G protein-coupled receptor, which involves in myocardial fibrosis by regulation of calcium homeostasis. Calhex231, the CaSR inhibitor, is not clear whether it regulates myocardial fibrosis in DCM. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts were used to observe the role of Calhex231. In vivo experiments showed that in the T1D group, contractile dysfunction and the deposition of collagen I and III were obvious after 12 weeks. In vitro experiments, we found that high glucose (HG) could increase the expression of CaSR, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) collagen I/III, matrix metalloproteinase-2 (MMP-2), MMP9, along with cardiac fibroblast migration and proliferation. We further demonstrated that CaSR activation increased intracellular Ca2+ concentration and upregulated the expression of Itch (atrophin-1 interacting protein 4), which resulted in increasing the ubiquitination levels of Smad7 and upregulating the expression of p-Smad2, p-Smad3. However, treatment with Calhex231 clearly inhibited the above-mentioned changes. Collectively these results suggest that Calhex231 could inhibit Itch-ubiquitin proteasome and TGF-ß1/Smads pathways, and then depress the proliferation of cardiac fibroblasts, along with the reduction deposition of collagen, alleviate glucose-induced myocardial fibrosis. Our findings indicate an important new mechanism for myocardial fibrosis, and suggest Calhex231 would be a new therapeutic agent for the treatment of DCM.


Assuntos
Benzamidas/farmacologia , Cicloexilaminas/farmacologia , Cardiomiopatias Diabéticas/patologia , Fibrose/tratamento farmacológico , Miocárdio/patologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Animais , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/metabolismo , Glucose/metabolismo , Coração , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais , Miocárdio/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitinas/metabolismo
13.
Am J Physiol Endocrinol Metab ; 317(2): E312-E326, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211620

RESUMO

Diabetic patients are more susceptible to myocardial ischemia damage than nondiabetic patients, with worse clinical outcomes and greater mortality. The mechanism may be related to glucose metabolism, mitochondrial homeostasis, and oxidative stress. Pyridostigmine may improve vagal activity to protect cardiac function in cardiovascular diseases. Researchers have not determined whether pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice. In the present study, autonomic imbalance, myocardial damage, mitochondrial dysfunction, and oxidative stress were exacerbated in isoproterenol-stimulated diabetic mice, revealing the myocardial vulnerability of diabetic mice to injury compared with mice with diabetes or exposed to isoproterenol alone. Compared with normal mice, the expression of glucose transporters (GLUT)1/4 phosphofructokinase (PFK) FB3, and pyruvate kinase isoform (PKM) was decreased in diabetic mice, but increased in isoproterenol-stimulated normal mice. Following exposure to isoproterenol, the expression of (GLUT)1/4 phosphofructokinase (PFK) FB3, and PKM decreased in diabetic mice compared with normal mice. The downregulation of SIRT3/AMPK and IRS-1/Akt in isoproterenol-stimulated diabetic mice was exacerbated compared with that in diabetic mice or isoproterenol-stimulated normal mice. Pyridostigmine improved vagus activity, increased GLUT1/4, PFKFB3, and PKM expression, and ameliorated mitochondrial dysfunction and oxidative stress to reduce myocardial damage in isoproterenol-stimulated diabetic mice. Based on these results, it was found that pyridostigmine may reduce myocardial vulnerability to injury via the SIRT3/AMPK and IRS-1/Akt pathways in diabetic mice with isoproterenol-induced myocardial damage. This study may provide a potential therapeutic target for myocardial damage in diabetic patients.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas/prevenção & controle , Glucose/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , Brometo de Piridostigmina/farmacologia , Animais , Metabolismo dos Carboidratos/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/fisiologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Brometo de Piridostigmina/uso terapêutico
14.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100876

RESUMO

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. METHODS: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. RESULTS: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. CONCLUSION: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.


Assuntos
Restrição Calórica/métodos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Angiotensina II/metabolismo , Animais , Glicemia , Carbazóis/farmacologia , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Masculino , Malondialdeído/sangue , Mesoporfirinas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Protoporfirinas/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo
15.
Eur J Pharmacol ; 858: 172393, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31085240

RESUMO

Diabetic cardiomyopathy (DCM) is one of the major cardiac complications in diabetic patients and a major reason for the death of diabetic patients. Obeticholic acid (OCA) is a semi-synthetic bile acid analogue. The objective of the present study was to investigate the possible cardio-protective effect of OCA against DCM. db/db diabetic mice were given OCA with or without injection of LV-short hairpin farnesoid X receptor (shFXR), and general glucose and lipid metabolism, myocardial morphology and function, myocardial fibrosis, inflammation and oxidative stress were evaluated. We found that OCA significantly ameliorated metabolic dysfunctions. Moreover, OCA attenuated morphological injury of cardiac tissue, restored the abnormal changes of hemodynamic variables and echocardiographic parameters. The Sirius-Red staining of cardiac tissue and mRNA expression of fibrotic biomarkers, including connective tissue growth factor, osteopontin, Transforming growth factor-ß1, atrial natriuretic peptide, Collagen Ⅰ, and Collagen Ⅲ were decreased by OCA. Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were reduced by OCA. Moreover, OCA decreased oxidant products and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and the expression and activities of antioxidant enzymes. Injection of LV-shFXR downregulated FXR expression and inhibited all these beneficial effects of OCA. FXR is major target that mediated that beneficial effect of OCA. In summary, FXR/Nrf2 signaling was involved in OCA-induced amelioration of metabolic disorder, oxidative stress, inflammation, fibrosis and myocardial dysfunction. Our findings provide new evidence for the interaction of FXR and Nrf2 signaling and novel option for the intervention of DCM.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Cardiomiopatias Diabéticas/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Ácido Quenodesoxicólico/farmacologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Fibrose , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
16.
Int Heart J ; 60(3): 512-520, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30971629

RESUMO

Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes mellitus. Reactive oxygen species produced excessively in diabetes mellitus cause necrosis, apoptosis, ferroptosis, inflammation, and fibrosis of the myocardium as well as impair the cardiac structure and function. It is increasingly clear that oxidative stress is a principal cause of diabetic cardiomyopathy. The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) activates the transcription of more than 200 genes in the human genome. Most of the proteins translated from these genes possess anti-oxidant, anti-inflammatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic actions. There is a growing body of evidence indicating that NRF2 and its target genes are crucial in preventing high glucose-induced oxidative damage in diabetic cardiomyopathy. Recently, many natural and synthetic activators of NRF2 are shown to possess promising therapeutic effects on diabetic cardiomyopathy in animal models of diabetic cardiomyopathy. Targeting NRF2 signaling by pharmacological entities is a potential approach to ameliorating diabetic cardiomyopathy. However, the persistent high expression of NRF2 in cancer tissues also protects the growth of cancer cells. This "dark side" of NRF2 increases the challenges of using NRF2 activators to treat diabetic cardiomyopathy. In addition, some NRF2 activators were found to have off-target effects. In this review, we summarize the current status and challenges of NRF2 as a potential therapeutic target for diabetic cardiomyopathy.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Ensaios Clínicos como Assunto , Cardiomiopatias Diabéticas/metabolismo , Humanos , Estresse Oxidativo , Transdução de Sinais/efeitos dos fármacos
17.
J Ethnopharmacol ; 238: 111857, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30959142

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Astragalus membranaceus (Fisch.) Bunge (AM) has been utilized for the treatment of diabetes mellitus and its complications for centuries. Astragalus polysaccharides (APS), the main bioactive ingredient extracted from the root of AM, is prescribed widely in China and has definite cardioprotective effect during diabetic cardiomyopathy (DCM). Endoplasmic reticulum (ER) stress-induced apoptosis played a crucial role in the progression of DCM. However, the regulatory mechanisms of APS on ER stress pathway haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to identify the effect of APS on cardiomyocyte apoptosis and to investigate the mechanisms for the anti-apoptotic effect of APS during DCM. MATERIALS AND METHODS: DCM rat model was induced by intraperitoneal streptozotocin (STZ) injection and treated with APS for 16 weeks. Cardiac function, pathological changes and apoptotic cells were assessed by echocardiography, hematoxylin-eosin (HE) staining and TUNEL assay, respectively. Expressions of key molecules in ER stress pathway were detected by Western blot analysis. Cardiomyocytes were exposed to high glucose (HG) and treated with APS for 24 h. Cell viability, apoptosis and protein expressions were assessed by MTT, flow cytometer and Western blot analysis, respectively. Moreover, lentivirus over-expressing (OE) C/EBP homologous protein (CHOP) was employed to further investigate the causative role of ER stress pathway in APS-mediated effect on cardiomyocyte apoptosis. RESULTS: In vivo, the results demonstrated that APS could improve heart function and attenuate myocardial apoptosis in DCM rat model. Further study demonstrated that APS could down-regulate the protein expressions of activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK) related factors of ER stress pathway. In vitro, APS significantly inhibit HG stimulated H9C2 cell apoptosis and the expressions of ATF6 and PERK related proteins of ER stress pathway. However, after CHOP-OE lentivirus transfection, the protective effects of APS were diminished as increased apoptotic rate and higher expression of CHOP. CONCLUSIONS: APS could attenuate cardiomyocyte apoptosis via down-regulating the expression of ATF6 and PERK related factors of ER stress pathway in DCM rats and HG-stimulated H9C2 cells.


Assuntos
Astrágalo (Planta) , Cardiotônicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cardiomiopatias Diabéticas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Polissacarídeos , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Ratos Sprague-Dawley , eIF-2 Quinase/metabolismo
19.
J Biol Chem ; 294(20): 8218-8226, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30952701

RESUMO

Excessive activation of the renin-angiotensin system (RAS) in diabetic cardiomyopathy (DCM) provokes a series of structural and functional abnormalities, and causes ventricular remodeling and heart failure in diabetes. (Pro)renin receptor (PRR) is a component of the RAS and has been reported to be up-regulated in some cardiovascular diseases. Furthermore, PRR blockade in some cardiovascular diseases, such as myocardial infarction and hypertension, has been demonstrated to reverse their pathogenesis. However, there have been few studies about the function of PRR in the pathogenesis of DCM. In this study, we hypothesized that PRR is involved in the pathogenesis of DCM and mediates myocardial injury in DCM. To explore the role of PRR in DCM, we evaluated the effects of PRR overexpression and knockdown on the DCM phenotype in vivo and in vitro The results show that PRR overexpression exacerbates myocardial injury and the inflammatory response in rats with DCM. Conversely, PRR knockdown alleviates myocardial fibrosis, apoptosis, and the inflammatory response, reversing the cardiac dysfunction in rats with DCM. In cell experiments, PRR overexpression also up-regulated the protein expression of collagen I and fibronectin, aggravated the inflammatory response, and increased the production of reactive oxygen species, whereas PRR knockdown had the opposite effect. Thus, PRR mediates myocardial injury, apoptosis, and the inflammatory response, likely through a PRR/extracellular signal-regulated kinase/reactive oxygen species pathway.


Assuntos
Apoptose , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Sistema de Sinalização das MAP Quinases , Miocárdio/metabolismo , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina , Animais , Colágeno Tipo I/biossíntese , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/patologia , Fibronectinas/biossíntese , Fibrose , Inflamação/metabolismo , Inflamação/patologia , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
20.
Ann Clin Lab Sci ; 49(1): 97-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814084

RESUMO

PURPOSE: The objective of this research was to explore the effect of dioscin on myocardium in streptozotocin (STZ)-induced diabetic rats and the underlying mechanisms. METHODS: Diabetic rat model was established by a single intravenous injection of streptozocin (STZ). The rats were divided into 5 groups: control group, control+dioscin group, model group (diabetes), DDL group (diabetic rats treated with 100 µg/kg/day dioscin) and DDH group (diabetic rats treated with 200 µg/kg/day dioscin). Each group was continuously intervened for 6 weeks. Hemodynamic parameters were detected and pathological alterations of myocardium were observed by hematoxylin-eosin (HE) staining. Inflammatory response and related proteins in the NO-sGC-cGMP-PKG pathway were detected by western blot. RESULTS: Dioscin treatment can increase ejection fraction (EF) and decrease left ventricular end-diastolic pressure (LVEDP) as well as time constant of left ventricular pressure decay (Tau) parameters in diabetic rats, suggesting the improvement of left ventricular function. By histopathology observation, we found that dioscin treatment can also improve myocardial histological lesions caused by diabetes. In addition, the levels of inflammatory cytokines TGF-ß1, TNF-α and IL-1ß of the model group were remarkably higher than those in the control group (p<0.01), while after being treated with dioscin these cytokines were obviously decreased (p<0.05). The levels of PDE-5, PKG and p-VASP in the diabetic rats were significantly declined after being treated by dioscin in a dose-dependent manner (p<0.05). CONCLUSION: Dioscin may prevent the myocardial injury in diabetic rats by up-regulating NO-sGC-cGMP-PKG pathway.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Diosgenina/análogos & derivados , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Diosgenina/farmacologia , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/prevenção & controle , Ratos , Ratos Sprague-Dawley
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