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1.
Arq. bras. cardiol ; 116(3): 415-422, Mar. 2021. graf
Article in English, Portuguese | LILACS | ID: biblio-1248864

ABSTRACT

Resumo Fundamento: É sabido que a resistência à insulina e a hiperglicemia são causas patológicas importantes no desenvolvimento de cardiomiopatia diabética (CMD). Entretanto, seus mecanismos moleculares precisos na patogênese da CMD ainda não estão claros. Objetivos: Estudos recentes revelam que os microRNAs (miRNAs) desempenham papéis essenciais na patogênese da CMD. Este projeto tem o objetivo de determinar os papéis de miR-34a e miR-125b na morte celular de cardiomiócitos causada por hiperglicemia. Métodos: Cardiomiócitos primários de ratos foram isolados e expostos a concentrações de glicose normais e altas. A viabilidade das células foi medida utilizando-se o ensaio MTT. As expressões de miR-34a e miR-125b foram detectadas por qRT-PCR. Alvos potenciais de miR-34a e miR-125b foram previstos pelo www.Targetscan.org, e validados a partir de tecidos cardíacos humanos. Um p<0,05 foi considerado significância estatística. Resultados: Demonstra-se neste estudo que o miR-34a e o miR-125b têm resposta celular reduzida no coração humano diabético. Além disso, os dados in vitro de cardiomiócitos primários de ratos demonstraram que o tratamento com glicose alta em curto prazo estimula a expressão de miR-34a e miR-125b. Demonstrou-se que, em condições de glicose alta, os cardiomiócitos de ratos apresentaram metabolismo de glicose intracelular, e a captação de glicose e a produção de lactato aumentaram significativamente. Foi identificado que as principais enzimas metabólicas da glicose, hexoquinase 2 (HK2) e lactato desidrogenase-A (LDHA) eram alvos diretos de miR-125b e miR-34a, respectivamente. A superexpressão de miR-125b e miR-34a poderia evitar a morte de celular de cardiomiócitos causada por hiperglicemia. Por fim, a recuperação de HK2 e LDHA em cardiomiócitos com superexpressão de miR-125b e miR-34a restaurou a sensibilidade de cardiomiócitos à hiperglicemia. Conclusões: Nossos resultados propõem um mecanismo molecular para proteção cardiovascular diabética mediada por microRNA e contribuirão para o desenvolvimento de estratégias de tratamento de disfunção cardiovascular associada a diabetes.


Abstract Background: It is well-known that insulin resistance and hyperglycemia are important pathological causes for the development of diabetic cardiomyopathy (DCM). However, its precise molecular mechanisms in the pathogenesis of DCM remain unclear. Objectives: Recent studies reveal that microRNAs (miRNA) play essential roles in the pathogenesis of DCM. This project aimed to determine the roles of miR-34a and miR-125b in hyperglycemia-induced cardiomyocyte cell death. Methods: Rat primary cardiomyocytes were isolated and exposed to normal and high concentrations of glucose. Cell viability was measured using MTT assay. Expressions of miR-34a and miR-125b were detected by qRT-PCR. Potential targets of miR-34a and miR-125b were predicted from www.Targetscan.org and validated from human heart tissues. A statistical significance of p<0.05 was considered. Results: The present study shows that miR-34a and miR-125b are downregulated in a human diabetic heart. Moreover, in vitro data from rat primary cardiomyocytes showed that short-term high glucose treatment stimulates miR-34a and miR-125b expressions. Under high glucose, it was found that rat cardiomyocytes displayed increased intracellular glucose metabolism, and glucose uptake and lactate production were significantly increased. It was also found that the key glucose metabolic enzymes, Hexokinase 2 (HK2) and Lactate dehydrogenase-A (LDHA), were direct targets of miR-125b and miR-34a, respectively. Overexpression of miR-125b and miR-34a could prevent hyperglycemia-induced cardiomyocyte cell death. Finally, the restoration of HK2 and LDHA in miR-125b and miR-34a overexpressed cardiomyocytes recovered the cardiomyocytes' sensitivity to hyperglycemia. Conclusion: Our results proposed a molecular mechanism for the microRNA-mediated diabetic cardiovascular protection and will contribute to developing treatment strategies for diabetes-associated cardiovascular dysfunction.


Subject(s)
Animals , Rats , MicroRNAs/genetics , Hyperglycemia , Cell Death , Myocytes, Cardiac , Glucose
2.
Article in Chinese | WPRIM | ID: wpr-911186

ABSTRACT

Objective:To evaluate the relationship between silence information regulator 1 (SIRT1) and signal transducers and activators of transcription 3 (STAT3) acetylation during high glucose-induced cardiac microvascular endothelial cell injury.Methods:Cardiac microvascular endothelial cells of Sprague-Dawley rats were cultured.The cells at the logarithmic growth phase were selected and divided into 3 groups ( n=24 each) using a random number table method: control group (C group), high glucose group (HG group) and high glucose+ SIRT1 agonist SRT1720 group (HG+ SRT group). The cardiac microvascular endothelial cells were seeded in a 6- or 96-well cell culture plate at a density of 2×10 5 cells/ml.When the cell density reached 50%, the culture medium was then replaced with high-glucose (glucose 33 mmol/L) DMEM culture medium containing with 10% fetal bovine serum and 1% double antibody in HG and HG+ SRT groups.In group HG+ SRT, 20 μmol/L SRT1720 was added simultaneously, and the cells were cultured at 37 ℃ in an incubator with 5% CO 2 for 24 h. The cell viability was determined by CCK-8 assay, the activity of superoxide dismutase (SOD) was detected using a spectrophotometer, the levels of lactic dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor-β (TNF-β) in the supernatant were detected by enzyme-linked immunosorbent assay, and the expression of SIRT1, acetylated STAT3 (ac-STAT3) and phosphorylated STAT3 (p-STAT3) was determined by Western blot. Results:Compared with C group, the cell viability and SOD activity were significantly decreased, levels of LDH, IL-6 and TNF-β in the supernatant were increased, expression of SIRT1 was down-regulated, and expression of ac-STAT3 and p-STAT3 was up-regulated in group HG and group HG+ SRT ( P<0.05). Compared with group HG, the cell viability and SOD activity were significantly increased, levels of LDH, IL-6 and TNF-β in the supernatant were decreased, expression of SIRT1 was up-regulated, and expression of ac-STAT3 and p-STAT3 was down-regulated in group HG+ SRT ( P<0.05). Conclusion:SIRT1 can alleviate high glucose-induced cardiac microvascular endothelial cell injury by promoting STAT3 deacetylation.

3.
Article in English | WPRIM | ID: wpr-811150

ABSTRACT

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca²⁺ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.


Subject(s)
Adenosine Triphosphate , Adiponectin , Autophagy , Diabetes Mellitus , Diabetic Cardiomyopathies , Heart Failure , Mitochondria , Mitochondrial Dynamics , Oxidative Stress , Reactive Oxygen Species , Regeneration , Sirtuins
4.
Article in English | WPRIM | ID: wpr-811138

ABSTRACT

BACKGROUND: Recent studies have shown that microRNAs (miRNAs) are involved in the process of cardiomyocyte apoptosis. We have previously reported that granulocyte-colony stimulating factor (G-CSF) ameliorated diastolic dysfunction and attenuated cardiomyocyte apoptosis in a rat model of diabetic cardiomyopathy. In this study, we hypothesized a regulatory role of cardiac miRNAs in the mechanism of the anti-apoptotic effect of G-CSF in a diabetic cardiomyopathy rat model.METHODS: Rats were given a high-fat diet and low-dose streptozotocin injection and then randomly allocated to receive treatment with either G-CSF or saline. H9c2 rat cardiomyocytes were cultured under a high glucose (HG) condition to induce diabetic cardiomyopathy in vitro. We examined the extent of apoptosis, miRNA expression, and miRNA target genes in the myocardium and H9c2 cells.RESULTS: G-CSF treatment significantly decreased apoptosis and reduced miR-34a expression in diabetic myocardium and H9c2 cells under the HG condition. G-CSF treatment also significantly increased B-cell lymphoma 2 (Bcl-2) protein expression as a target for miR-34a. In addition, transfection with an miR-34a mimic significantly increased apoptosis and decreased Bcl-2 luciferase activity in H9c2 cells.CONCLUSION: Our results indicate that G-CSF might have an anti-apoptotic effect through down-regulation of miR-34a in a diabetic cardiomyopathy rat model.


Subject(s)
Animals , Apoptosis , Diabetic Cardiomyopathies , Diet, High-Fat , Down-Regulation , Glucose , Granulocyte Colony-Stimulating Factor , In Vitro Techniques , Luciferases , Lymphoma, B-Cell , MicroRNAs , Models, Animal , Myocardium , Myocytes, Cardiac , Rats , Streptozocin , Transfection
6.
Article in Chinese | WPRIM | ID: wpr-755688

ABSTRACT

Objective To investigate the therapeutic effect and mechanism of non-mitogenic acid fibroblast growth factor 1( NMFGF1) on diabetic cardiomyopathy ( DCM) by using PEG-modified nano-liposomes combined with ultrasound-targeted microbubble destruction technique ( UTMD ) . Methods The NMFGF1 loaded PEG-modified nano-liposomes were prepared by a water-in-water emulsion method and their quality inspections were also investigated. Type 1 diabetes animal model was induced by intraperitoneal injection of streptozotocin ( 70 mg/kg) in male SD rats. The diabetic rats were raised twelve weeks after the diabetes model was established and DCM rats were selected by ultrasonic heart function examination. After two weeks of intervention, all rats were kept for another two weeks and then underwent transthoracic echocardiography examination. The rats were sacrificed and myocardial tissue was obtained to quantify myocardial collagen fraction ( CVF ) and cardiac myocyte apoptotic index by Sirius red staining and TUNEL staining. Results NMFGF1-loaded PEG-nano-liposomes showed a good morphology and 90.3%± 1.4% NMFGF1 encapsulation efficiency. Compared with DCM group, NMFGF1group, and NMFGF1-PEG-nano-liposomes group, NMFGF1-loaded PEG-nano-liposome plus UTMD group showed increased left ventricular end diastolic diameter (LVIDd) [(7.36±0.42) vs (5.75±0.24), (6.64±0.27), (6.72±0.24)mm, all P<0.05]and leftventricularfractionshortening(LVFS) [(50±3) vs (33±2), (44±5), (43±3)mm, all P<0.05], and decreased left ventricular posterior wall thickness (LVPW) [(1.65±0.07) vs (1.89±0.08), (1.73±0.11), (1.73 ±0.07) mm, all P<0.05], with decreased CVF and apoptotic index(all P<0.05). Conclusion PEG-nano-liposomes combining with UTMD technique has a greater translational potential in the delivery of NMFGF1 for the treatment of DCM by attenuating oxidative stress-induced injury and may provide a promising strategy for treating diabetes cardiomyopathy.

7.
Chinese Journal of Cardiology ; (12): 820-828, 2019.
Article in Chinese | WPRIM | ID: wpr-796616

ABSTRACT

Objective@#To investigate whether microRNA(miR)-214 can improve hyperglycemia induced pyroptosis in H9c2 cells through targeting caspase-1.@*Methods@#H9c2 cells of rats those in good growth condition were selected and incubated into the T25 culture bottle after digestion and passage. Cells were cultured in an incubator at 37 ℃ with 5%CO2, repeat passage was made after cell density reached about 80%, The 5th to 8th generations of cells were selected for the subsequent experiments. To observe the effect of overexpression of miR-214 on pyroptosis and caspase-1 expression in H9c2 cells induced by hyperglycemia, the cells were divided into 4 groups: Control group(H9c2 cells cultured normally), Hyperglycemia group (HG group, 50 mmol/L glucose was used to intervene H9c2 cells for 24 hours), miR-214 mimics+hyperglycosis group (mimics+HG group, H9c2 cells were transfected with miR-214 mimics for 24 hours and then treated with 50 mmol/L hyperglycosis for 24 hours), miR-214 mimic-negative control+hyperglycaemic group(MNC+HG group, H9c2 cells were transfected with miR-214 mimic-negative control for 24 hours and then treated with 50 mmol/L hyperglycaemic for 24 hours). In order to further verify the anti-pyroptosis effect of miR-214 was mediated by targeted inhibition on caspase-1, cells overexpressing caspase-1 were used in the rescue experiment. The cells overexpressing caspase-1 were divided into 4 groups: Hyperglycemia group (HG group, 50 mmol/L glucose was used to intervene H9c2 cells for 24 hours), miR-214 mimics+hyperglycosis group (mimics+HG group, H9c2 cells were transfected with miR-214 mimics for 24 hours and then treated with 50 mmol/L hyperglycosis for 24 hours), miR-214 mimics+hyperglycosis+recombinant adenovirus (Ad-caspase-1-EGFP) group with caspase-1 gene and EGFP green fluorescent protein expression (mimics+HG+Ad-caspase-1-EGFP group, H9c2 cells were transfected with caspase-1-green fluorescent protein-carrying adenovirus for 48 hours, followed by transfection of miR-214 mimics for 24 hours, and then treated with 50 mmol/L hyperglycaemia for 24 hours), miR-214 mimics+HG+Ad-EGFP empty virus group (mimics+HG+Ad-EGFP group, H9c2 cells were transfected with empty adenovirus containing green fluorescent protein for 48 hours, followed by transfection with miR-214 mimics for 24 hours, and then treated with 50 mmol/L hyperglycosis for 24 hours). The mRNA expression levels of miRNA-214 and caspase-1 in cells were detected by real-time quantitative PCR. The expression and localization of caspase-1 protein were detected by immunofluorescence assay. Western blot was used to detect protein expression levels of procaspase-1, cleaved caspase-1, NLRP3 and ACS with β-actin as internal reference. The secretion of IL-1β and IL-18 in cell culture medium was detected by ELISA. The correlation between miR-214 and caspase-1 was detected by double luciferase reporter gene.@*Results@#(1) The mRNA expression levels of miR-214 and caspase-1 in each group: the mRNA expressions of miR-214 in HG group and MNC+HG group were significantly lower than that in control group(P<0.05). The mRNA expression of miR-214 in mimics+HG group was significantly higher than that in control group (P<0.05). The mRNA expression levels of caspase-1 in HG group and MNC+HG group were significantly higher than that in control group(P<0.05). The mRNA expression level of caspase-1 in mimics+HG group was lower than that in control group(P<0.05). (2) The expression of caspase-1 in each group: the green fluorescence intensity in the control group was weak, which was strong in the HG group and MNC+HG group. The green fluorescence expression was weaker in mimics+HG group than in HG group. (3) ASC and NLRP3 protein expression levels in each group: ASC and NLRP3 protein expression levels in HG group and MNC+HG group were higher than those in control group(P<0.05). ASC and NLRP3 protein expression levels were significantly lower in mimics+HG group than in mimics+HG group (P<0.05). (4) The secretion of IL-1β and IL-18 in the cell culture medium of each group: the content of IL-1β and IL-18 in the cell culture medium of HG group and MNC+HG group was significantly higher than that of control group (P<0.05). The content of IL-1β and IL-18 in the cell culture medium of mimics+HG group was significantly lower than that of the HG group (P<0.05). (5) Correlation between miR-214 and caspase-1: miR-214 specifically binds to caspase-1 3 ′UTR. Meanwhile, Western blot results showed that cleaved caspase-1 protein expression levels were significantly higher in both HG group and MNC+HG group than in control group (P<0.05). The levels of cleaved caspase-1 were significantly lower in mimics+HG group than in HG group (P<0.05). There was no significant difference in procaspase-1 expression among groups (P>0.05). (6) The expression levels of procaspase-1, cleaved caspase-1, ASC and NLRP3 in each group in rescue experiment: there was no significant difference in the expression of procaspase-1 in each group (P>0.05). Cleaved caspase-1, ASC and NLRP3 protein expressions were significantly lower in mimics+HG group than in HG group (P<0.05). However, cleaved caspase-1, ASC and NLRP3 protein expressions were significantly higher in mimics+HG+ Ad-caspase-1-EGFP group than in mimics+HG group (P<0.05). (7) The expression of IL-1β and IL-18 in rescue experiment: the secretions of IL-1β and IL-18 in the cell culture medium of the mimics+HG group were significantly lower than that of HG group (P<0.05), which were significantly higher in mimics+HG+Ad-caspase-1-EGFP group than in mimics+HG group (P<0.05).@*Conclusion@#miR-214 can improve the hyperglycemia induced pyroptosis in H9c2 cells by targeted inhibition of the caspase-1.

8.
Rev. urug. cardiol ; 32(3): 264-276, dic. 2017. tab
Article in Spanish | LILACS | ID: biblio-903594

ABSTRACT

La enfermedad coronaria, la hipertensión arterial y la diabetes son factores de riesgo independientes para el desarrollo de insuficiencia cardíaca y muerte. La cardiomiopatía diabética (CMD) es una de las etiologías frecuentes de cardiopatía en pacientes con diabetes tipo 1 y tipo 2. Si bien se suele plantear la CMD como la causa de la cardiopatía cuando se excluyen la hipertensión arterial, las valvulopatías y la enfermedad arterial coronaria aterotrombótica, estas coexisten con frecuencia e incluso también con la neuropatía autónoma cardiovascular. En los pacientes con CMD se puede demostrar mediante tests serológicos y por imagen alteraciones a nivel molecular, metabólico, mitocondrial, celular y tisular con infiltración grasa del músculo cardíaco, vinculadas a hiperglicemia, hiperinsulinemia y resistencia a la insulina, así como a lipotoxicidad por ácidos grasos libres, que son responsables del desarrollo de la CMD. Esta entidad primero determina disfunción diastólica del ventrículo izquierdo, más tarde disfunción sistólica e insuficiencia cardíaca. Se diagnostica mediante estudios serológicos de marcadores biológicos múltiples y por técnicas de imagen que evidencian la disfunción ventricular y mejoran la predicción pronóstica de enfermedad cardiovascular en diabéticos. En base a dichas pruebas se ha propuesto una clasificación por estadios o fenotipos clínicos de la CMD, que apunta a su diagnóstico precoz. Puede ser asintomática o ser responsable de síntomas y manifestaciones severas tales como insuficiencia cardíaca, arritmias y muerte súbita. Se puede asociar a hipertensión arterial, a enfermedad coronaria, a otras manifestaciones de microangiopatía y macroangiopatía aterotrombótica y a mortalidad cardiovascular. La prevención y el tratamiento intensivo multifactorial y personalizado de la diabetes, de todas sus alteraciones metabólicas y de la cardiopatía, mejoran la calidad y prolongan la vida. Se espera que investigaciones recientes, en proceso y futuras, determinen portentosos avances en la prevención y en el tratamiento de la CMD, que constituye una de las serias amenazas a la salud de la humanidad.


Coronary heart disease, hypertension and diabetes mellitus are independent risk factors for heart failure and death. Diabetic cardiomyopathy (DCM) is one of the common etiologies of cardiac disease in patients with diabetes type 1 or 2. Although DCM is often considered as the cause of heart disease when arterial hypertension, valvulopathies and atherothrombotic coronary artery are excluded, they coexist frequently, as well as with cardiovascular neuropathy. In patients with DCM, serological and imaging tests can show alterations at the molecular, metabolic, mitochondrial, cellular and tissue levels with fatty infiltration of the heart muscle, linked to hyperglycemia, hyperinsulinemia, insulin resistance, and lipotoxicity by fatty free acids, which are responsible for the development of the cardiomyopathy. The DCM first determines left ventricular diastolic dysfunction, later systolic dysfunction and heart failure. It is diagnosed by serological tests of multiple biological markers and by imaging tests that demonstrate ventricular dysfunction and improve the prognostic prediction of cardiovascular disease in diabetics. Based on these tests, a classification by stages or clinical phenotypes of DCM, which aims at its early diagnosis, has been proposed. It can be asymptomatic or be responsible for symptoms and severe manifestations such as heart failure, arrhythmias and sudden death, and may associate hypertension, coronary disease, other manifestations of microangiopathy and atherothrombotic macroangiopathy and cardiovascular mortality. The prevention and intensive multifactorial and personalized treatment of diabetes and all its metabolic and cardiac alterations, improve quality and prolong life. It is expected that ongoing and future research will determine breakthroughs in the prevention and treatment of DCM, which is one of the serious threats to the health of mankind.


Subject(s)
Humans , Diabetes Mellitus, Type 2/complications , Diabetic Cardiomyopathies/diagnosis , Diabetic Cardiomyopathies/physiopathology , Diabetic Cardiomyopathies/therapy , Diagnostic Techniques and Procedures , Diabetes Mellitus, Type 1/complications
9.
Article in English | WPRIM | ID: wpr-161480

ABSTRACT

The proposal that diabetes plays a role in the development of heart failure is supported by the increased risk associated with this disease, even after correcting for all other known risk factors. However, the precise mechanisms contributing to the condition referred to as diabetic cardiomyopathy have remained elusive, as does defining the disease itself. Decades of study have defined numerous potential factors that each contribute to disease susceptibility, progression, and severity. Many recent detailed reviews have been published on mechanisms involving insulin resistance, dysregulation of microRNAs, and increased reactive oxygen species, as well as causes including both modifiable and non-modifiable risk factors. As such, the focus of the current review is to highlight aspects of each of these topics and to provide specific examples of recent advances in each area.


Subject(s)
Diabetic Cardiomyopathies , Disease Susceptibility , Energy Metabolism , Heart Failure , Insulin Resistance , Metabolic Diseases , MicroRNAs , Mitochondria, Heart , Reactive Oxygen Species , Risk Factors , Stress, Physiological
10.
Article in English | WPRIM | ID: wpr-217842

ABSTRACT

The global burden of diabetes mellitus and its related complications are currently increasing. Diabetes mellitus affects the heart through various mechanisms including microvascular impairment, metabolic disturbance, subcellular component abnormalities, cardiac autonomic dysfunction, and a maladaptive immune response. Eventually, diabetes mellitus can cause functional and structural changes in the myocardium without coronary artery disease, a disorder known as diabetic cardiomyopathy (DCM). There are many diagnostic tools and management options for DCM, although it is difficult to detect its development and effectively prevent its progression. In this review, we summarize the current research regarding the pathophysiology and pathogenesis of DCM. Moreover, we discuss emerging diagnostic evaluation methods and treatment strategies for DCM, which may help our understanding of its underlying mechanisms and facilitate the identification of possible new therapeutic targets.


Subject(s)
Coronary Artery Disease , Diabetes Mellitus , Diabetic Cardiomyopathies , Heart , Heart Failure , Myocardium
11.
Chinese Journal of Cardiology ; (12): 427-433, 2017.
Article in Chinese | WPRIM | ID: wpr-808673

ABSTRACT

Objective@#The therapeutic effect of acid fibroblast growth factor 1(FGF1) on rats with diabetic cardiomyopathy (DCM) was evaluated by using nano-liposomes combined with ultrasound-targeted microbubble destruction technique (UTMD).@*Methods@#The FGF1-loaded nano-liposomes were prepared by water-in-water emulsion method combined with lyophilization technique.TypeⅠdiabetes model was induced by intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) in 60 male SD rats.Sixteen weeks later, diabetic rats were randomly divided into: placebo group (saline treatment), FGF1 group, FGF1-loaded nano-liposomes group, and FGF1-loaded nano-liposomes plus UTMD group (n=15 each). After two weeks of intervention followed by 2 weeks intervention stop, all rats underwent cardiac catheterization, and the left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP) and the maximal increase/decrease rate of left ventricular pressure (LV±dp/dtmax) were measured.Then, the rats were sacrificed and myocardial tissue were obtained for Masson trichrome staining, TUNEL apoptotic staining and CD31 immunohistochemistry staining to quantify myocardial collagen fraction (CVF), cardiac myocyte apoptotic index and myocardial microvascular density (MVD).@*Results@#(1)Scanning electron microscope results revealed good morphology and FGF1 encapsulation efficiency (84.3±2.8)% with high stability and dispensability of FGF1 loaded nano-liposomes.(2)The hemodynamic evaluation showed that LVESP, LV + dp/dtmax and LV -dp/dtmax were all significantly higher, while LVEDP was significantly lower in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group(all P<0.05). (3)The Masson trichrome staining demonstrated that CVF was significantly higher in all DCM groups than in control group and was significantly lower in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05). (4)The CD31 immunohistochemical staining results showed that MVD was significantly lower in all DCM groups than in control group and was significantly higher in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05). (5)The TUNEL results showed that apoptotic index was significantly higher in all DCM groups than in control group and was significantly lower in the FGF1-loaded nano-liposome + UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05).@*Conclusion@#FGF1 nano-liposomes combining with UTMD technique can significantly improve cardiac functions and attenuate myocardial CVF and apoptosis and enhance myocardial MVD in DCM rats.

12.
Article in Chinese | WPRIM | ID: wpr-503562

ABSTRACT

BACKGROUND:Brahma-related gene 1 (Brg1), a catalytic subunit of an important chromatin remodeling complex, has been considered as a key nuclear transcriptional factor, and tends to be decreased in diabetic cardiomyopathy. OBJECTIVE:To construct an adenovirus vector carrying Brg1, and observe its protective role in oxidative stress induced-cardiomyocyte apoptosis. METHODS:The recombinant adenovirus plasmid was linearized and transfected into HEK293 cel s using Fugene HD for packaging and amplification. The adenovirus particles were further purified, quantified, and sequential y transfected to cardiomyocytes of neonatal Sprague-Dawley rats. The Adeno-EGFP transfected and non-transfected cardiomyocytes were used as control group. 24 hours later, the transfection efficiency was observed by fluorescent microscope, and expressions of Brg1 mRNA and protein were detected by quantified PCR and western blotting. After treatment with 100 μmol/L H2O2 for 12 hours, the expressions of Brg1 protein and cleaved-Caspase 3 were measured by western blotting, and cel apoptosis was analyzed by flow cytometry. RESULTS AND CONCLUSION:(1) The recombinant adenovirus vector of Brg1 had been successful y transfected into cardiomyocytes with higher expressions of Brg1 mRNA and protein, and the transfection efficiency reached more than 90%. (2) After H2O2 treatment, the Brg1 was significantly down-regulated in contrast to the up-regulation of cleaved-Caspase 3;the flow cytometry data showed that the apoptotic cel s were increased. But in Adeno-Brg1 transfected cardiomyocytes, the H2O2 induced cel apoptosis was significantly decreased compared with non-transfected cel s and empty vector transfected cel s. (3) These results suggest that oxidative stress can directly inhibit the Brg1 expression, and overexpression of Brg1 can protect the cardiomyocytes from cel apoptosis induced by oxidative stress.

13.
Article in Chinese | WPRIM | ID: wpr-488061

ABSTRACT

Objective To investigate the protective effects of left ventricular myocardial perfusion after delivery of acidic fibroblast growth factor (aFGF) in rats with diabetic cardiomyopathy (DCM) by using ultrasound‐targeted microbubble destruction ( UTMD ) with real‐time myocardial contrast echocardiography( RT‐MCE) . Methods Among 64 male SD rats ,52 rats were randomly selected and were induced DCM by streptozotocin through intraperitoneal injecting ,the other rats as normal control group . DCM rats were randomly divided into the DCM model group ,aFGF only group ,SonoVue‐aFGF group and the SonoVue‐aFGF+ UTMD group in this study . The aFGF only group rats were injected with aFGF solution through tail vein ,the SonoVue‐aFGF group were injected with SonoVue‐aFGF solution through tail vein and SonoVue‐aFGF+ UTMD group rats were injected with SonoVue‐aFGF solution through tail vein and using UTMD simultaneously . All rats underwent conventional echocardiography and RT‐MCE exams before and 4 weeks after intervention . Left ventricular ejection fraction ( LVEF) and left ventricular fraction shortening( LVFS ) were measured by conventional echocardiography . The plateau intensity ( A ) ,initial slope of the curve (β) and myocardial blood flow ( A ×β) of left ventricular anterior wall at the papillary muscle level were measured in left ventricular short‐axis view by RT‐MCE . Results Before intervention , LVEF and LVFS in the DCM model group ,aFGF only group ,SonoVue‐aFGF group and the SonoVue‐aFGF+UTMD group were significantly lower than in the normal control group ( P 0 .05) ,however A and A × β in the SonoVue‐aFGF+ UTMD group were significantly increased than those in the DCM model group( P < 0 .01) . Compared with the same group before intervention ,A and A ×βin the SonoVue‐aFGF+UTMD group were higher ( P <0 .05) and these in the DCM model group were lower during four weeks after intervention ( P < 0 .05) . Conclusions Acidic fibroblast growth factor delivered by using UTMD can improve the left ventricular myocardial perfusion in diabetic cardiomyopathy rats .

14.
Article in Chinese | WPRIM | ID: wpr-850090

ABSTRACT

Objective To study the effects of exogenous hydrogen sulfide (H2S) on myocardial fibrosis of diabetic mice and the mechanism thereof. Methods Twenty-four male adult C57BL/6J mice were randomly divided into 4 groups (6 each): normal control group (NC group), diabetes mellitus group (ALX group), diabetes mellitus treated with low dose NaHS group (ALX+LDNaHS group) and diabetes mellitus treated with high dose NaHS group (ALX+HDNaHS group). The diabetic mouse model was established by intraperitoneal injection of alloxan at 200mg/kg. Mice in NC group and ALX group drank tap water freely everyday, and in ALX+LDNaHS group and ALX+HDNaHS group were provided with sodium hydrosulfide (NaHS, donor of H2S, 30μmol/L and 90μmol/L, respectively) in drinking water, and the histological specimens of mice were examined 8 weeks later. The morphological changes of cardiac tissue were examined with HE staining. The expressions of mRNA of p38mitogen-activated protein kinase (p38MAPK) and nuclear transcription factor kappa B p65 (NF-κB p65) were detected by Real-time PCR, and the expressions of p-p38MAPK, p-NF-κB p65 and Collagen I proteins were detected by Western blotting. Results Compared with NC group, the expression of collagen increased and there was fibrillation in the myocardial matrix, the expressions of mRNA of p38MAPK and NF-κB p65 increased obviously (P<0.01), the protein expressions of p-p38MAPK, p-NF-κB p65 and Collagen I increased significantly (P<0.01) in ALX group; after intervention of H2S, the cardiac muscle fibers were parallel arranged, the expression of collagen was visibly decreased and there was less fibrillation in the myocardial matrix, the expressions of mRNA of p38MAPK and NF-κB p65 were obviously decreased (P<0.01), the protein expressions of p-p38MAPK, p-NF-κB p65 and Collagen I were significantly decreased (P<0.01), and more improvement was observed in ALX+HDNAHS group than in ALX+LDNAHS group (P<0.05). Conclusion H2S can ameliorate myocardial fibrosis in diabetic mice, which might be related to the regulation of p38MAPK and NF-κB p65-mediated inflammatory reaction.

15.
Korean Circulation Journal ; : 266-272, 2015.
Article in English | WPRIM | ID: wpr-28562

ABSTRACT

Patients with diabetes have an increased risk for development of cardiomyopathy, even in the absence of well known risk factors like coronary artery disease and hypertension. Diabetic cardiomyopathy was first recognized approximately four decades ago. To date, several pathophysiological mechanisms thought to be responsible for this new entity have also been recognized. In the presence of hyperglycemia, non-enzymatic glycosylation of several proteins, reactive oxygen species formation, and fibrosis lead to impairment of cardiac contractile functions. Impaired calcium handling, increased fatty acid oxidation, and increased neurohormonal activation also contribute to this process. Demonstration of left ventricular hypertrophy, early diastolic and late systolic dysfunction by sensitive techniques, help us to diagnose diabetic cardiomyopathy. Traditional treatment of heart failure is beneficial in diabetic cardiomyopathy, but specific strategies for prevention or treatment of cardiac dysfunction in diabetic patients has not been clarified yet. In this review we will discuss clinical and experimental studies focused on pathophysiology of diabetic cardiomyopathy, and summarize diagnostic and therapeutic approaches developed towards this entity.


Subject(s)
Calcium , Cardiomyopathies , Coronary Artery Disease , Diabetes Mellitus , Diabetic Cardiomyopathies , Fibrosis , Glycosylation , Heart Failure , Humans , Hyperglycemia , Hypertension , Hypertrophy, Left Ventricular , Reactive Oxygen Species , Risk Factors
16.
São Paulo; s.n; 2014. [40] p. ilus, tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-870805

ABSTRACT

Introdução: A Doença Pulmonar Obstrutiva Crônica (DPOC) está freqüentemente associada a comorbidades crônicas como a doença cardiovascular, o diabetes mellitus e a hipertensão. O presente estudo tem por objetivo investigar as alterações morfológicas e funcionais no coração secundárias ao enfisema pulmonar em ratos diabéticos. Métodos: Ratos Wistar machos adultos (200 ± 20 g, n = 36) foram destinados à avaliação ecocardiográfica, análise morfométrica do coração e pulmões e análise da taxa de sobrevida. O diabetes mellitus foi induzido por aloxana (42 mg/kg, iv) 10 dias antes da indução do enfisema pulmonar por instilação de elastase (0,25 UI/100 g de peso corpóreo). Um grupo de ratos diabéticos recebeu tratamento com insulina NPH (4 UI antes da elastase, seguido de 2 UI/dia, 50 dias). Os experimentos foram realizados 50 dias após a instilação. Resultados: Ratos diabéticos e respectivos controles instilados com elastase apresentaram aumentos similares no diâmetro médio alveolar, cujos valores correlacionam-se positivamente com aumentos na espessura da parede (p=0,0022), na área da cavidade (p=0,0001) e espessura dos cardiomiócitos (p=0,0001) do ventriculo direito (VD). Ratos tornados diabéticos por injeção de aloxana exibiram redução na espessura da parede do ventrículo esquerdo (VE), no septo interventricular (IV) e na espessura dos cardiomiócitos. Estas variáveis morfométricas associaram-se à redução da fração de encurtamento do VE (p < 0,05) e a aumento no tempo de relaxamento isovolumétrico do VE (p < 0,05). A taxa de sobrevida reduziu-se de 80% em ratos diabéticos a 40% em ratos diabéticos instilados com elastase (p < 0,05). Conclusões: O diabetes por aloxana em ratos não modifica a hipertrofia do VD secundária ao enfisema pulmonar, porém induz disfunção ventricular esquerda. A manifestação de ambas as doenças, diabetes mellitus e enfisema pulmonar, reduz substancialmente a taxa de sobrevida, enfatizando a condição de comorbidade na coexistência de...


Background: Chronic Obstructive Pulmonary Disease (COPD) is often associated with chronic comorbid conditions of cardiovascular disease, diabetes mellitus and hypertension. This study aimed to investigate morphological and functional alterations of the heart secondary to chronic emphysema in diabetic rats. Methods: Adult male Wistar rats (200 ± 20 g, n=36) were used for echocardiographic measurements, morphometric analyses of the heart and lungs, and survival rate. Diabetes mellitus was induced by alloxan (42 mg/kg, iv) 10 days before the induction of pulmonary emphysema by the instillation of elastase (0.25 IU/100 g body weight). A group of diabetic rats was treated with NPH insulin (4 IU before elastase, plus 2 IU/day, 50 days). Experiments were performed 50 days after instillation. Results: Both elastase-instilled diabetic rats and matching controls exhibited similar increases in mean alveolar diameter, which are positively correlated with increases in RV wall thickness (p=0.0022), cavity area (p=0.0001), and cardiomyocyte thickness (p=0.0001). Alloxan-diabetic rats demonstrated a reduction in left ventricular (LV) wall, IV septum, and cardiomyocyte thickness, associated with a reduction in LV fractional shortening (p<0.05), and an increase in LViv relaxation time (p < 0.05). Survival rate decreased from 80% in diabetic rats to 40% in elastase-instilled diabetic rats. Conclusions: Alloxan diabetes did not affect RV hypertrophy secondary to chronic emphysema, but induced LV dysfunction. The association of diabetes and emphysema substantially reduced the survival rate, emphasizing the comorbid condition of the coexistence of diabetes and COPD.


Subject(s)
Animals , Male , Adult , Rats , Diabetes Mellitus , Diabetic Cardiomyopathies , Hypertrophy, Right Ventricular , Mortality , Pancreatic Elastase , Pulmonary Emphysema , Rats, Wistar
17.
Chinese Journal of Pathophysiology ; (12): 1098-1102,1109, 2014.
Article in Chinese | WPRIM | ID: wpr-599288

ABSTRACT

AIM:To observe the expression of angiogenesis factors in the myocardial tissue of streptozotocin-induced diabetic rats .METHODS:The diabetic rat model was induced by intraperitoneal injection of streptozotocin .After 12 weeks, the cardiac function was measured by MPA cardiac function analysis system .The myocardial collagen volume fraction ( CVF) was assessed by Masson staining .The capillary vessels was quantified as the ratio of capillary to myocyte (C/M) using CD31 immunostaining.The expression levels of vascular endothelial growth factor (VEGF), angiopoietin ( Ang)-1, endostatin and Ang-2 were observed by Western blotting .RESULTS:Compared with normal control group , the left ventricular end-diastolic pressure (LVEDP) was evidently increased (P0.05).CONCLUSION:Im-balances between the angiogenic factors (VEGF and Ang-1) and anti-angiogenic factors (endostatin) may play an impor-tant role in the pathogenesis of diabetic cardiomyopathy .

18.
Article in English | WPRIM | ID: wpr-222033

ABSTRACT

Diabetic cardiomyopathy (DCM), as one of the major cardiac complications in diabetic patients, is known to related with oxidative stress that is due to a severe imbalance between reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) generation and their clearance by antioxidant defense systems. Transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in maintaining the oxidative homeostasis by regulating multiple downstream antioxidants. Diabetes may up-regulate several antioxidants in the heart as a compensative mechanism at early stage, but at late stage, diabetes not only generates extra ROS and/or RNS but also impairs antioxidant capacity in the heart, including Nrf2. In an early study, we have established that Nrf2 protect the cardiac cells and heart from high level of glucose in vitro and hyperglycemia in vivo, and in the following study demonstrated the significant down-regulation of cardiac Nrf2 expression in diabetic animals and patients. Using Nrf2-KO mice or Nrf2 inducers, blooming evidence has indicated the important protection by Nrf2 from cardiac pathogenesis in the diabetes. Therefore, this brief review summarizes the status of studies on Nrf2's role in preventing DCM and even other complications, the need for new and safe Nrf2 inducer screening and the precaution for the undesirable side of Nrf2 under certain conditions.


Subject(s)
Animals , Antioxidants , Diabetic Cardiomyopathies , Down-Regulation , Glucose , Heart , Homeostasis , Humans , Hyperglycemia , Mass Screening , Mice , NF-E2-Related Factor 2 , Oxidative Stress , Reactive Nitrogen Species , Reactive Oxygen Species , Transcription Factors
19.
Article in English | WPRIM | ID: wpr-69107

ABSTRACT

BACKGROUND AND OBJECTIVES: The aim of the present study was to evaluate left ventricle systolic and diastolic function, using tissue Doppler echocardiography (TDE), in relation to blood glucose status in prediabetic patients who had no evidence of heart disease by conventional echocardiography (CE). SUBJECTS AND METHODS: We included 60 patients (30 female, 30 male) and 20 healthy controls (10 male, 10 female). All participants were randomised into four groups according to their oral glucose tolerance test. Group-I consisted of those patients who had only impaired fasting glucose (IFG). group-II consisted of patients who had only impaired glucose tolerance (IGT) and group-III consisted of patients who had both IFG and IGT, that is so-called combined glucose intolerance. Group-IV included the healthy controls. All subjects underwent both CE and TDE. RESULTS: No significant differences were found among the four groups in terms of CE. There was no significant difference between group-IV and group-I with respect to the early peak diastolic velocity (Ea) of medial mitral annulus (11.65+/-0.66 vs. 9.72+/-1.58, p>0.05), whereas a statistically significant difference was found between group-IV and group-II (11.65+/-0.66 vs. 9.06+/-1.07, p<0.001) and between group-IV and group-III (11.65+/-0.66 vs. 9.74+/-1.09, p<0.05). CONCLUSION: Diastolic myocardial dysfunction in prediabetic patients may be identified by quantitative TDE before the appearance of CE indices of myocardial dysfunction.


Subject(s)
Blood Glucose , Diabetes Mellitus, Type 2 , Diabetic Cardiomyopathies , Echocardiography , Echocardiography, Doppler , Fasting , Female , Glucose , Glucose Intolerance , Glucose Tolerance Test , Heart Diseases , Heart Ventricles , Humans , Male
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