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1.
Vascul Pharmacol ; : 106651, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044414

RESUMO

Aspirin is a widely used drug with anti-coagulating and anti-inflammatory effects on atherosclerotic vascular disease. The goal of this study was to investigate expression of microRNA (miR) and changes in arachidonic acid (AA) metabolism in cardiac and surrounding fat mesenchymal stem cells (MSCs) treated with or without aspirin. Aspirin-targeted endogenous lipid metabolites that impact specific miRNA expression were examined by mass spectrometry. The pattern of miR expression was characterized using a microarray of 1100 miRs. There were a dozen miRs expressed differentially in MSCs from human myocardium and peri-myocardial fat tissue at baseline, including hsa-miR-1307-3p, 765, 4739, 3613-3p, 4281, 6816-5p, 2861, and 146b-5p. After exposure to aspirin, cardiac MSCs expressed an array of of miRs (eg, hsa-miR-4734, 10a-5p, 4267, 3197, and 3182), while generation of their endogenous AA metabolites was depressed. However, in the peri-cardiac adipose tissue-derived MSCs, treatment with the same doses of aspirin caused mild changes in the miR expression levels. In conclusion, MSCs from human myocardium and peri-myocardial fat tissue have respond differentially to aspirin treatment by alterations in miR expression and AA metabolism. The study further raises an intriguing issue as to whether the copious amounts of aspirin taken worldwide by patients with cardiovascular disease may have direct impacts on their heart repair processes by regulation of stromal cell miR expression and AA metabolism.

2.
J Cell Mol Med ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970899

RESUMO

Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE-/- (Ins2+/Akita : ApoE-/- ) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age- and sex-matched C57/BL6 control mice, the aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed increased aortic stiffness. The aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed greater expression of VCAM-1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III-to-elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita :ApoE-/- mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F-actin and α-smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)-1 and transcription factor NFAT5, which control the expression of genes activated by high glucose-induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co-expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.

3.
Regen Med ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829095

RESUMO

Aim: To determine the efficacy and safety of intracoronary infusion of autologous bone marrow mesenchymal stem cells (MSCINJ) in combination with intensive atorvastatin (ATV) treatment for patients with anterior ST-segment elevation myocardial infarction-elevation myocardial infarction. Patients & methods: The trial enrolls a total of 100 patients with anterior ST-elevation myocardial infarction. The subjects are randomly assigned (1:1:1:1) to receive routine ATV (20 mg/d) with placebo or MSCsINJ and intensive ATV (80 mg/d) with placebo or MSCsINJ. The primary end point is the absolute change of left ventricular ejection fraction within 12 months. The secondary end points include parameters in cardiac function, remodeling and regeneration, quality of life, biomarkers and clinical outcomes. Results & conclusion: The trial will implicate the essential of cardiac micro-environment improvement ('fertilizing') for cell-based therapy. Clinical Trial Registration: NCT03047772.

4.
Sci Rep ; 9(1): 14035, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575906

RESUMO

Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-ß-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.

5.
Am J Transl Res ; 11(7): 4214-4231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396330

RESUMO

The SDF-1/CXCR4 signaling plays a critical role in the trafficking of mesenchymal stem cells (MSCs) to the sites of tissue damage. Our recent study demonstrated that atorvastatin (ATV) treatment improved the survival of MSCs, and ATV pretreated MSCs (ATV-MSCs) exhibited enhanced engraftment to injured myocardium. In this study, we investigated whether combined treatment with ATV and ATV-MSCs enhances cardiac repair and regeneration by activating SDF-1/CXCR4 signaling in a rat model of acute myocardial infarction. Rats were randomized into eight groups: the Sham, AMI control and 6 other groups that were subjected to AMI followed by treatment with MSCs, ATV, ATV+MSCs, ATV-MSCs, ATV+ATV-MSCs, ATV+ATV-MSCs+AMD3100 (SDF-1/CXCR4 antagonist), respectively. ATV+ATV-MSCs significantly potentiated targeted recruitment of MSCs to peri-infarct myocardium and resulted in further improvements in cardiac function and reduction in scar size compared with MSCs treatment alone at 4-week after AMI. More importantly, the cardioprotective effects conferred by ATV+ATV-MSCs were almost completely abolished by AMD3100 treatment. Together, our study demonstrated that ATV+ATV-MSCs significantly enhanced the targeted recruitment and survival of transplanted MSCs, and resulted in subsequent cardiac function improvement by augmenting SDF-1/CXCR4 signaling.

6.
Curr Mol Med ; 19(4): 294-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30907314

RESUMO

BACKGROUND: Hydrogen has been shown to exert a bioactive effect on the myocardium. This study examined the signalling pathways for hydrogen attenuating ischaemia-reperfusion injury. METHODS: In total, 20 male Wistar rats were evaluated for the effects of hydrogen-rich water on ischaemia-reperfusion in hearts. Left ventricular tissue was taken for screening and analysis of active protein factors by protein chip technology. The enrichment of the KEGG pathway was obtained by using the Gene Ontology (GO) enrichment principle. The expression of JAK2, STAT1, STAT3, p-STAT1, p-JAK2, p-STAT3 in rat myocardium was detected by Western blot analysis and immunohistochemistry. The apoptosis rates of the control and hydrogen-rich water groups were detected by TUNEL staining. RESULTS: The expression levels of 25 proteins, including five transduction pathways, were downregulated in the hydrogen-rich water group. The expression levels of p- JAK2/JAK2, p-STAT3/STAT3 were upregulated in the hydrogen-rich water group compared with the control group, and p-STAT1/STAT1 was downregulated in the hydrogen-rich water group compared with the control group. Furthermore, the apoptosis rate was significantly decreased in the hydrogen-rich water group, as well. CONCLUSION: Hydrogen-rich water may inhibit the apoptosis of cardiomyocytes after ischaemia-reperfusion by upregulating the expression of the JAK2-STAT3 signalling pathway, which reduces ischaemia-reperfusion injury.

7.
Coron Artery Dis ; 30(4): 297-302, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888975

RESUMO

AIM: This study aimed to define the relationship between pulse pressure (PP) and coronary artery calcification (CAC), a proven surrogate marker for coronary heart disease. PATIENTS AND METHODS: A total of 170 participants 50-70 years of age from 11 villages of Yunnan Province of China were enrolled randomly into this study. They were examined routinely for diastolic and systolic blood pressure, PP, and CAC. RESULTS: The average PP in the CAC-positive group was significantly higher than that in the CAC-negative group. In the positive CAC group, there were significantly positive correlations between PP and CAC score, volume, mass, as well as density. The area under the receiver operating characteristic curve analysis showed that PP performed well in predicting CAC. CONCLUSION: In conclusion, among the rural people of southwest of China, PP correlates positively with the coronary calcium Agatston score, volume, mass, and density. PP predicted CAC as well as Framingham Risk Score. The measurement of PP widening may serve as an alternative and convenient method for assessing CAC risk in rural populations with poor accessibility and economic disadvantage over coronary computed tomography scanning.

8.
Transl Stroke Res ; 10(4): 413-427, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30191468

RESUMO

Extracellular superoxide dismutase (EC-SOD) has been implicated in regulation of vascular function but its underlying molecular mechanism is largely unknown. These two-step experiments investigate whether hemagglutinating virus of Japan envelope (HVJ-E) vector-mediated EC-SOD gene delivery might protect against neointima formation, vascular inflammation, and reactive oxygen species (ROS) generation, and also explore cell growth signaling pathways. The first in-vitro experiment was performed to assess the transfection efficacy and safety of HVJ-E compared to lipofectamine®. Results revealed that HVJ-E has higher transfection efficiency and lower cytotoxicity than those of lipofectamine®. Another in-vivo study initially used balloon denudation to rat carotid artery, then delivered EC-SOD cDNA through the vector of HVJ-E. Arterial section with H&E staining from the animals 14 days after balloon injury showed a significant reduction of intima-to-media area ratio in EC-SOD transfected arteries when compared with control (empty vector-transfected arteries) (p < 0.05). Arterial tissue with EC-SOD gene delivery also exhibited lower levels of ROS, as assessed by fluorescent microphotography with dihydroethidium staining. Quantitative RT-PCR revealed that EC-SOD gene delivery significantly diminished mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß (p < 0.05 in all comparisons). An immunoblotting assay from vascular smooth muscle cell (VSMC) cultures showed that the EC-SOD transfected group attenuated the activation of MEK1/2, ERK1/2, and Akt signaling significantly. In conclusion, EC-SOD overexpression by HVJ-E vector inhibits neointima hyperplasia, inflammation, and ROS level triggered by balloon injury. The modulation of cell growth-signaling pathways by EC-SOD in VSMCs might play an important role in these inhibitory effects.


Assuntos
Lesões das Artérias Carótidas/terapia , Técnicas de Transferência de Genes , Neointima/terapia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Vírus Sendai , Superóxido Dismutase/administração & dosagem , Proteínas do Envelope Viral/administração & dosagem , Animais , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/metabolismo , Células Cultivadas , Células HeLa , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/terapia , Inflamação/genética , Inflamação/metabolismo , Inflamação/terapia , Masculino , Neointima/genética , Neointima/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vírus Sendai/genética , Superóxido Dismutase/biossíntese , Superóxido Dismutase/genética , Proteínas do Envelope Viral/genética
9.
Adv Exp Med Biol ; 1088: 347-368, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30390260

RESUMO

Muscle atrophy in aging is characterized by progressive loss of muscle mass and function. Muscle mass is determined by the balance of synthesis and degradation of protein, which are regulated by several signaling pathways such as ubiquitin-proteasome system, autophagy-lysosome systems, oxidative stress, proinflammatory cytokines, hormones, and so on. Sufficient nutrition can enhance protein synthesis, while exercise can improve the quality of life in the elderly. This chapter will discuss the epidemiology, pathogenesis, as well as the current treatment for aging-induced muscular atrophy.


Assuntos
Envelhecimento/patologia , Músculo Esquelético/patologia , Atrofia Muscular/fisiopatologia , Autofagia , Citocinas/fisiologia , Humanos , Proteínas Musculares , Atrofia Muscular/epidemiologia , Atrofia Muscular/terapia , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/fisiologia , Transdução de Sinais , Ubiquitina/fisiologia
10.
Vascul Pharmacol ; 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29425894

RESUMO

Diabetic macroangiopathy - a specific form of accelerated atherosclerosis - is characterized by intra-plaque new vessel formation due to excessive/abnormal neovasculogenesis and angiogenesis, increased vascular permeability of the capillary vessels, and tissue edema, resulting in frequent atherosclerotic plaque hemorrhage and plaque rupture. Mechanisms that may explain the premature and rapidly progressive nature of atherosclerosis in diabetes are multiple, and to a large extent still unclear. However, mechanisms related to hyperglycemia certainly play an important role. These include a dysregulated vascular regeneration. In addition, oxidative and hyperosmolar stresses, as well as the activation of inflammatory pathways triggered by a dysregulated activation of membrane channel proteins aquaporins, have been recognized as key events. Here, we review recent knowledge of cellular and molecular pathways of macrovascular disease related to hyperglycemia in diabetes. We also here highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment.

11.
Chin Med J (Engl) ; 131(5): 544-552, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29483388

RESUMO

Background: Our previous studies have shown that Tongxinluo (TXL), a compound Chinese medicine, can decrease myocardial ischemia-reperfusion injury, protect capillary endothelium function, and lessen cardiac ventricle reconstitution in animal models. The aim of this study was to illuminate whether TXL can improve hypercholesterolemia-impaired heart function by protecting artery endothelial function and increasing microvascular density (MVD) in heart. Furthermore, we will explore the underlying molecular mechanism of TXL cardiovascular protection. Methods: After intragastric administration of TXL (0.1 ml/10 g body weight) to C57BL/6J wild-type mice (n = 8) and ApoE-/- mice (n = 8), total cholesterol, high-density lipoprotein-cholesterol, very-low-density lipoprotein (VLDL)-cholesterol, triglyceride, and blood glucose levels in serum were measured. The parameters of heart rate (HR), left ventricular diastolic end diameter, and left ventricular systolic end diameter were harvested by ultrasonic cardiogram. The left ventricular ejection fraction, stroke volume, cardiac output, and left ventricular fractional shortening were calculated. Meanwhile, aorta peak systolic flow velocity (PSV), end diastolic flow velocity, and mean flow velocity (MFV) were measured. The pulsatility index (PI) and resistant index were calculated in order to evaluate the vascular elasticity and resistance. The endothelium-dependent vasodilatation was evaluated by relaxation of aortic rings in response to acetylcholine. Western blotting and real-time quantitative reverse transcription polymerase chain reaction were performed for protein and gene analyses of vascular endothelial growth factor (VEGF). Immunohistochemical detection was performed for myocardial CD34 expression. Data in this study were compared by one-way analysis of variance between groups. A value of P < 0.05 was considered statistically significant. Results: Although there was no significant decrease of cholesterol level (F = 2.300, P = 0.240), TXL inhibited the level of triglyceride and VLDL (F = 9.209, P = 0.024 and F = 9.786, P = 0.020, respectively) in ApoE-/- mice. TXL improved heart function of ApoE-/- mice owing to the elevations of LVEF, SV, CO, and LVFS (all P < 0.05). TXL enhanced aortic PSV and MFV (F = 10.774, P = 0.024 and F = 11.354, P = 0.020, respectively) and reduced PI of ApoE-/- mice (1.41 ± 0.17 vs. 1.60 ± 0.17; P = 0.037). After incubation with 10 µmol/L acetylcholine, the ApoE-/- mice treated with TXL aortic segment relaxed by 44% ± 3%, significantly higher than control group mice (F = 9.280, P = 0.040). TXL also restrain the angiogenesis of ApoE-/- mice aorta (F = 21.223, P = 0.010). Compared with C57BL/6J mice, the MVD was decreased in heart tissue of untreated ApoE-/- mice (54.0 ± 3.0/mm2 vs. 75.0 ± 2.0/mm2; F = 16.054, P = 0.010). However, TXL could significantly enhance MVD (65.0 ± 5.0/mm2 vs. 54.0 ± 3.0/mm2; F = 11.929, P = 0.020) in treated ApoE-/- mice. In addition, TXL obviously increased the expression of VEGF protein determined by Western blot (F = 20.247, P = 0.004). Conclusions: TXL obviously improves the ApoE-/- mouse heart function from different pathways, including reduces blood fat to lessen atherosclerosis; enhances aortic impulsivity, blood supply capacity, and vessel elasticity; improves endothelium-dependent vasodilatation; restraines angiogenesis of aorta-contained plaque; and enhances MVD of heart. The molecular mechanism of MVD enhancement maybe relate with increased VEGF expression.


Assuntos
Apolipoproteínas E/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Western Blotting , Ecocardiografia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Imuno-Histoquímica , Lipoproteínas VLDL/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Volume Sistólico/efeitos dos fármacos , Triglicerídeos/sangue
12.
Adv Exp Med Biol ; 998: 187-206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28936741

RESUMO

Cardiovascular diseases resulting from ischemic heart diseases remain to be the main causes of heart failure and death despite significant advances in medical treatment. The development of new therapies for heart failure is thus required to improve the outcome in these patients, and this has led to the development of cell-based therapies. Animal studies showed interesting results using various cell types. Some stem cell based therapies have been tested in clinical trials. Although the results were encouraging, challenges remain. Tumorigenic potential, immune rejection, and low engraftment and survival rate of transplant cells have hindered the widespread application of stem cells in the clinic. Fortunately, exosome based therapy could avoid these problems associated with cell therapy. Future research should focus on how various molecules are sorted into exosomes and this information will help to design better exosomes for treatment of cardiovascular diseases. Recent studies suggest that exosome content can vary depending on how cells are challenged. It would be important to find out exactly what types of cellular stress is needed for producing most useful exosomes. Alternatively, specific molecules can be introduced into exosomes by genetic engineering in order to treat specific conditions and to improve efficacy.


Assuntos
Doenças Cardiovasculares/cirurgia , Células-Tronco Embrionárias/transplante , Exossomos/transplante , Miocárdio/patologia , Miócitos Cardíacos/transplante , Regeneração , Transplante de Células-Tronco , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Células-Tronco Embrionárias/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação da Expressão Gênica , Humanos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Recuperação de Função Fisiológica , Transdução de Sinais , Transplante de Células-Tronco/efeitos adversos
13.
Circ Res ; 120(12): 1903-1915, 2017 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-28461455

RESUMO

RATIONALE: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. OBJECTIVE: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. METHODS AND RESULTS: Acta2-/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2-/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2-/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. CONCLUSIONS: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.


Assuntos
Actinas/deficiência , Angiotensina II/metabolismo , Aorta Torácica/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Receptor Tipo 1 de Angiotensina/biossíntese , Actinas/efeitos dos fármacos , Actinas/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Células Cultivadas , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/genética
14.
Vascul Pharmacol ; 90: 1-7, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28137665

RESUMO

Diabetic microangiopathy, including retinopathy, is characterized by abnormal growth and leakage of small blood vessels, resulting in local edema and functional impairment of the depending tissues. Mechanisms leading to the impairment of microcirculation in diabetes are multiple and still largely unclear. However, a dysregulated vascular regeneration appears to play a key role. In addition, oxidative and hyperosmolar stress, as well as the activation of inflammatory pathways triggered by advanced glycation end-products and toll-like receptors, have been recognized as key underlying events. Here, we review recent knowledge on cellular and molecular pathways of microvascular disease in diabetes. We also highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment.


Assuntos
Angiopatias Diabéticas/metabolismo , Microvasos/metabolismo , Animais , Permeabilidade Capilar , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/terapia , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Microcirculação , Microvasos/patologia , Microvasos/fisiopatologia , Neovascularização Patológica , Estresse Oxidativo , Prognóstico , Transdução de Sinais , Receptores Toll-Like/metabolismo
15.
Biomed Res Int ; 2017: 4150705, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28203568

RESUMO

Mesenchymal stem cells (MSCs) repair infarcted heart through paracrine mechanism. We sought to compare the effectiveness of MSCs and MSC-derived exosomes (MSC-Exo) in repairing infarcted hearts and to identify how MSC-Exo mediated cardiac repair is regulated. In a rat myocardial infarction model, we found that MSC-Exo inhibited cardiac fibrosis, inflammation, and improved cardiac function. The beneficial effects of MSC-Exo were significantly superior compared to that of MSCs. To explore the potential mechanisms underlying MSC-Exo's effects, we performed several in vitro experiments and miRNA-sequence analysis. MSC-Exo stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis induced by H2O2, and inhibited TGF-ß induced transformation of fibroblast cell into myofibroblast. Importantly, novel miRNA sequencing results indicated that MSC-Exo and MSCs have similar miRNA expression profile, which could be one of the reasons that MSC-Exo can replace MSCs for cardiac repair. In addition, the expression of several miRNAs from MSC-Exo was significantly different from that of MSCs, which may explain why MSC-Exo has better therapeutic effect than MSCs. In conclusion, this study demonstrates that MSC-Exo could be used alone to promote cardiac repair and are superior to MSCs in repairing injured myocardium.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/biossíntese , Infarto do Miocárdio/terapia , Regeneração/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Exossomos/genética , Exossomos/metabolismo , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica/genética , Comunicação Parácrina/genética , Ratos
16.
Stem Cell Reports ; 8(2): 290-304, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28111280

RESUMO

Maternal nicotine exposure causes alteration of gene expression and cardiovascular programming. The discovery of nicotine-medicated regulation in cardiogenesis is of major importance for the study of cardiac defects. The present study investigated the effect of nicotine on cardiac gene expression and epigenetic regulation during myocardial differentiation. Persistent nicotine exposure selectively inhibited expression of two cardiac genes, Tbx5 and Gata4, by promoter DNA hypermethylation. The nicotine-induced suppression on cardiac differentiation was restored by general nicotinic acetylcholine receptor inhibition. Consistent results of Tbx5 and Gata4 gene suppression and cardiac function impairment with decreased left ventricular ejection fraction were obtained from in vivo studies in offspring. Our results present a direct repressive effect of nicotine on myocardial differentiation by regulating cardiac gene suppression via promoter DNA hypermethylation, contributing to the etiology of smoking-associated cardiac defects.


Assuntos
Diferenciação Celular/genética , Metilação de DNA/efeitos dos fármacos , Fator de Transcrição GATA4/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células Musculares/citologia , Células Musculares/metabolismo , Nicotina/farmacologia , Proteínas com Domínio T/genética , Animais , Sequência de Bases , Linhagem Celular , Sobrevivência Celular/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Corpos Embrioides , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Feminino , Masculino , Camundongos , Antagonistas Nicotínicos/farmacologia , Gravidez , Regiões Promotoras Genéticas , Ratos , Receptores Nicotínicos/metabolismo
17.
Vascul Pharmacol ; 87: 6-9, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27720893

RESUMO

Characterized by progressive elevation of mean pulmonary artery pressure and pulmonary vascular resistance, pulmonary arterial hypertension (PAH) is an important health problem that contributes to right heart failure. Pulmonary arterial remodeling and constriction are two prominent features of PAH. It is a traditional view that increasing pulmonary blood flow and pressure, aerobic exercise does more harm than good to the pulmonary vasculature in PAH. However, recent studies have documented a potential benefit of low-intensity aerobic exercise for PAH patients. Here the current mini-review outlines the evidence and challenges for this additional tool in our armamentarium to combat this ominous disease.


Assuntos
Terapia por Exercício/métodos , Exercício/fisiologia , Hipertensão Pulmonar/terapia , Animais , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Resistência Vascular/fisiologia
18.
Nat Med ; 22(6): 657-65, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27183216

RESUMO

Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.


Assuntos
Aterosclerose/genética , Movimento Celular/genética , Miócitos de Músculo Liso/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Placa Aterosclerótica/genética , Animais , Aorta/metabolismo , Apolipoproteínas E/genética , Western Blotting , Linhagem da Célula , Sobrevivência Celular , Imunoprecipitação da Cromatina , Doença da Artéria Coronariana/metabolismo , Dieta Ocidental , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Miócitos de Músculo Liso/citologia , Fator 3 de Transcrição de Octâmero/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
J Cell Mol Med ; 20(4): 644-54, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26781745

RESUMO

Congenital heart disease (CHD) is a worldwide health problem, particularly in young populations. In spite of the advancement and progress in medical research and technology, the underlying causative factors and mechanisms of CHD still remain unclear. Bone morphogenetic protein receptor IA (ALK3) mediates the development of ventricular septal defect (VSD). We have recently found that paired box gene 8 (Pax8) may be the downstream molecule of ALK3. Paired box gene 8 plays an essential role in VSD, and apoptosis and proliferation imbalance leads to septal dysplasia. Recent studies have also disclosed that cellular senescence also participates in embryonic development. Whether programmed senescence exists in cardiac organogenesis has not ever been reported. We hypothesized that together with various biological processes, such as apoptosis, enhanced cellular senescence may occur actively in the development of Pax8 null mice murine hearts. In H9C2 myogenic cells, Pax8 overexpression can rescue caspase-dependent apoptosis induced by ALK3 silencing. Senescent cells and senescence-associated mediators in Pax8 knockout hearts increased compared with the wild-type ones in an age-dependent manner. These results suggest that Pax8 maybe the downstream molecule of ALK3, it mediates the murine heart development perhaps via cellular senescence, which may serve as a mechanism that compensates for the cell loss via apoptosis in heart development.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Comunicação Interventricular/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fator de Transcrição PAX8/genética , Animais , Animais Recém-Nascidos , Apoptose/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Linhagem Celular , Senescência Celular , Regulação da Expressão Gênica no Desenvolvimento , Comunicação Interventricular/metabolismo , Comunicação Interventricular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/genética , Miocárdio/patologia , Miócitos Cardíacos/patologia , Fator de Transcrição PAX8/deficiência , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
20.
Cardiovasc Diabetol ; 15: 18, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26822858

RESUMO

BACKGROUND: We tested the hypothesis that glucose-induced hyperosmolarity, occurring in diabetic hyperglycemia, promotes retinal angiogenesis, and that interference with osmolarity signaling ameliorates excessive angiogenesis and retinopathy in vitro and in vivo. METHODS AND RESULTS: We incubated human aortic (HAECs) and dermal microvascular endothelial cells (HMVECs) with glucose or mannitol for 24 h and tested them for protein levels and in vitro angiogenesis. We used the Ins2 Akita mice as a model of type 1 diabetes to test the in vivo relevance of in vitro observations. Compared to incubations with normal (5 mmol/L) glucose concentrations, cells exposed to both high glucose and high mannitol (at 30.5 or 50.5 mmol/L) increased expression of the water channel aquaporin-1 (AQP1) and cyclooxygenase (COX)-2. This was preceded by increased activity of the osmolarity-sensitive transcription factor Tonicity enhancer binding protein (TonEBP), and enhanced endothelial migration and tubulization in Matrigel, reverted by treatment with AQP1 and TonEBP siRNA. Retinas of Ins2 Akita mice showed increased levels of AQP1 and COX-2, as well as angiogenesis, all reverted by AQP1 siRNA intravitreal injections. CONCLUSIONS: Glucose-related hyperosmolarity seems to be able to promote angiogenesis and retinopathy through activation of TonEBP and possibly increasing expression of AQP1 and COX-2. Osmolarity signaling may be a target for therapy.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Retinopatia Diabética/enzimologia , Células Endoteliais/enzimologia , Glucose/metabolismo , Neovascularização Patológica , Animais , Aquaporina 1/genética , Aquaporina 1/metabolismo , Movimento Celular , Células Cultivadas , Diabetes Mellitus Tipo 1 , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Glucose/toxicidade , Humanos , Masculino , Manitol/toxicidade , Camundongos Endogâmicos C57BL , Concentração Osmolar , Interferência de RNA , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção
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