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1.
Nutrients ; 11(10)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591312

RESUMO

Diet plays a decisive role in heart physiology, with lipids having especial importance in pathology prevention and development. This study aimed to investigate how dietary lipids varying in lipid profile (virgin olive oil, sunflower oil or fish oil) affected the heart of rats during aging. Heart histopathology, mitochondrial morphometry, and oxidative status were assessed. Typical histopathological features associated with aging, such as valvular lesions, endomyocardical hyperplasia, or papillary muscle calcification, were found at a low extent in all the experimental groups. The most relevant finding was that inflammation registered by fish oil group was lower compared to the other treatments. At the ultrastructural level, heart mitochondrial area, perimeter, and aspect ratio were higher in fish oil-fed rats than in those fed on sunflower oil. Concerning oxidative stress markers, there were differences only in coenzyme Q levels and catalase activity, lower in sunflower oil-fed animals compared with those fed on fish oil. In summary, dietary intake for a long period on dietary fats with different fatty acids profile led to differences in some aspects associated with the aging process at the heart. Fish oil seems to be the fat most protective of heart during aging.


Assuntos
Óleos de Peixe/administração & dosagem , Cardiopatias/prevenção & controle , Longevidade , Mitocôndrias Cardíacas/ultraestrutura , Miocárdio/ultraestrutura , Azeite de Oliva/administração & dosagem , Óleo de Girassol/administração & dosagem , Fatores Etários , Ração Animal , Animais , Óleos de Peixe/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Azeite de Oliva/metabolismo , Estresse Oxidativo , Ratos Wistar , Óleo de Girassol/metabolismo , Fatores de Tempo
2.
Nanoscale ; 11(36): 16868-16878, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31482911

RESUMO

Ferritin is a protein that regulates the iron ions in humans by storing them in the form of iron oxides. Despite extensive efforts to understand the ferritin iron oxide structures, it is still not clear how ferritin proteins with a distinct light (L) and heavy (H) chain subunit ratio impact the biomineralization process. In situ graphene liquid cell-transmission electron microscopy (GLC-TEM) provides an indispensable platform to study the atomic structure of ferritin mineral cores in their native liquid environment. In this study, we report differences in the iron oxide formation in human spleen ferritins (HSFs) and human heart ferritins (HHFs) using in situ GLC-TEM. Scanning transmission electron microscopy (STEM) along with selected area electron diffraction (SAED) of the mineral core and electron energy loss spectroscopy (EELS) analyses enabled the visualization of morphologies, crystal structures and the chemistry of iron oxide cores in HSFs and HHFs. Our study revealed the presence of metastable ferrihydrite (5Fe2O3·9H2O) as a dominant phase in hydrated HSFs and HHFs, while a stable hematite (α-Fe2O3) phase predominated in non-hydrated HSFs and HHFs. In addition, a higher Fe3+/Fe2+ ratio was found in HHFs in comparison with HSFs. This study provides new understanding on iron-oxide phases that exist in hydrated ferritin proteins from different human organs. Such new insights are needed to map ferritin biomineralization pathways and possible correlations with various iron-related disorders in humans.


Assuntos
Compostos Férricos/metabolismo , Microscopia Eletrônica de Transmissão e Varredura , Miocárdio , Baço , Ferritinas , Grafite , Humanos , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Baço/metabolismo , Baço/ultraestrutura
3.
PLoS One ; 14(8): e0221512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430335

RESUMO

Laminopathies are tissue-selective diseases that affect differently in organ systems. Mutations in nuclear envelopes, emerin (Emd) and lamin A/C (Lmna) genes, cause clinically indistinguishable myopathy called Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy. Several murine models for EDMD have been generated; however, emerin-null (Emd) mice do not show obvious skeletal and cardiac muscle phenotypes, and Lmna H222P/H222P mutant (H222P) mice show only a mild phenotype in skeletal muscle when they already have severe cardiomyopathy. Thus, the underlying molecular mechanism of muscle involvement due to nuclear abnormalities is still unclarified. We generated double mutant (Emd-/-/LmnaH222P/H222P; EH) mice to characterize dystrophic changes and to elucidate interactions between emerin and lamin A/C in skeletal and cardiac muscles. As H222P mice, EH mice grow normally and have breeding productivity. EH mice showed severer muscle involvement compared with that of H222P mice which was an independent of cardiac abnormality at 12 weeks of age. Nuclear abnormalities, reduced muscle fiber size and increased fibrosis were prominent in EH mice. Roles of emerin and lamin A/C in satellite cells function and regeneration of muscle fiber were also evaluated by cardiotoxin-induced muscle injury. Delayed increases in myog and myh3 expression were seen in both H222P and EH mice; however, the expression levels of those genes were similar with control and regenerated muscle fiber size was not different at day 7 after injury. These results indicate that EH mouse is a suitable model for studying skeletal muscle involvement, independent of cardiac function, in laminopathies and an interaction between emerin and lamin A/C in different tissues.


Assuntos
Lamina Tipo A/genética , Proteínas de Membrana/deficiência , Músculo Esquelético/patologia , Miocárdio/patologia , Proteínas Nucleares/deficiência , Envelhecimento/patologia , Animais , Cardiotoxinas , Núcleo Celular/patologia , Núcleo Celular/ultraestrutura , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Músculo Esquelético/fisiopatologia , Músculo Esquelético/ultraestrutura , Miocárdio/ultraestrutura , Proteínas Nucleares/metabolismo , Fenótipo , Regeneração
4.
Int J Mol Med ; 44(4): 1255-1266, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432099

RESUMO

The primary mechanism underlying sepsis­induced cardiac dysfunction is loss of endothelial barrier function. Neuregulin­1 (NRG­1) exerts its functions on multiple targets. The present study aimed to identify the protective effects of NRG­1 in myocardial cells, including endothelial, anti­inflammatory and anti­apoptotic effects. Subsequent to lipopolysaccharide (LPS)­induced sepsis, rats were administered with either a vehicle or recombinant human NRG­1 (rhNRG­1; 10 µg/kg/day) for one or two days. H9c2 cardiomyoblasts were subjected to LPS (10 µg/ml) treatment for 12 and 24 h with or without rhNRG­1 (1 µg/ml). Survival rates were recorded at 48 h following sepsis induction. The hemodynamic method was performed to evaluate cardiac function, and myocardial morphology was observed. Von Willebrand Factor levels were detected using an immunofluorescence assay. Serum levels of tumor necrosis factor α, interleukin­6, intercellular cell adhesion molecule­1 and vascular endothelial growth factor were detected using an enzyme­linked immunosorbent assay; the reductase method was performed to detect serum nitric oxide levels. Apoptosis rates were determined using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Ras homolog family member A (RhoA) and Rho­associated protein kinase 1 (ROCK1) protein levels were assessed using western blotting. Transmission electron microscopy was used to observe endothelial cells and myocardial ultrastructure changes. Results revealed that NRG­1­treated rats displayed less myocardial damage compared with sham rats. NRG­1 administration strengthened the barrier function of the vasculature, reduced the secretion of endothelial­associated biomarkers and exerted anti­inflammatory and anti­apoptotic effects. In addition, NRG­1 inhibited RhoA and ROCK1 signaling. The results revealed that NRG­1 improves cardiac function, increases the survival rate of septic rats and exerts protective effects via multiple targets throughout the body. The present results contribute to the development of a novel approach to reverse damage to myocardial and endothelial cells during sepsis.


Assuntos
Cardiotônicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Neuregulina-1/farmacologia , Sepse/complicações , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/metabolismo , Cardiopatias/tratamento farmacológico , Cardiopatias/mortalidade , Testes de Função Cardíaca , Humanos , Mediadores da Inflamação , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia
5.
J Trace Elem Med Biol ; 56: 21-30, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442950

RESUMO

OBJECTIVE: Selenium(Se)is an important trace element for human health. Studies have shown that selenium deficiency and low protein(Pr) intake are the primary risk factors for Keshan disease.The relationship between the cardiac malfunction induced by these two risk factors and the mitochondria-mediated apoptotic pathway is poorly understood.This study aimed to determine the effect of selenium deficiency and low protein intake on the mitochondria-mediated apoptotic pathway. METHODS: In the present study, 120 weaning Wistar rats were randomly fed one of six different diets. The myocardial tissue sections were deparaffinized in water and subjected to hematoxylin-eosin staining. Mitochondrial changes in the myocardial tissue were observed and photographed using an H-7650 Hitachi transmission electron microscope. Levels of whole blood Se were measured using hydride generation atomic fluorescence spectrometry. Whole blood glutathione peroxidase (GSH-Px) activity was measured using a glutathione peroxidase cellular activity assay kit. Malondialdehyde (MDA), total-anti-oxidizing-capability(T-AOC)and reactive oxygen species(ROS)levels in serum and myocardial tissue were measured using MDA, T-AOC and ROS kits. Apoptosis was detected by immunohistochemistry. RESULTS: Experimental results showed that the selenium-deficient diet decreased serum selenium levels and GSH-PX activity, which caused severe cardiac dysfunction. Importantly, the levels of MDA and ROS in serum and myocardial tissue defects were significantly increased, where as total-anti-oxidizing-capability(T-AOC) levels were dramatically decreased as a result of the combination of selenium deficiency and low protein intake (P<0.05).The levels of cleaved caspase-9 and cleaved caspase-3 were enhanced, but the expression of B-cell lymphoma-2 (Bcl-2) was reduced (P<0.05). CONCLUSIONS: Our results suggest that selenium deficiency and low protein intake can cause oxidative stress in the myocardium and induce cell apoptosis via the mitochondria-mediated pathway.


Assuntos
Apoptose , Dieta com Restrição de Proteínas , Mitocôndrias/metabolismo , Selênio/deficiência , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Peso Corporal , Caspase 3/metabolismo , Caspase 9/metabolismo , Regulação da Expressão Gênica , Glutationa Peroxidase , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Selênio/sangue
6.
Proc Natl Acad Sci U S A ; 116(33): 16384-16393, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31358631

RESUMO

High-speed atomic force microscopy (HS-AFM) can be used to study dynamic processes with real-time imaging of molecules within 1- to 5-nm spatial resolution. In the current study, we evaluated the 3-state model of activation of cardiac thin filaments (cTFs) isolated as a complex and deposited on a mica-supported lipid bilayer. We studied this complex for dynamic conformational changes 1) at low and high [Ca2+] (pCa 9.0 and 4.5), and 2) upon myosin binding to the cTF in the nucleotide-free state or in the presence of ATP. HS-AFM was used to directly visualize the tropomyosin-troponin complex and Ca2+-induced tropomyosin movements accompanied by structural transitions of actin monomers within cTFs. Our data show that cTFs at relaxing or activating conditions are not ultimately in a blocked or activated state, respectively, but rather the combination of states with a prevalence that is dependent on the [Ca2+] and the presence of weakly or strongly bound myosin. The weakly and strongly bound myosin induce similar changes in the structure of cTFs as confirmed by the local dynamical displacement of individual tropomyosin strands in the center of a regulatory unit of cTF at the relaxed and activation conditions. The displacement of tropomyosin at the relaxed conditions had never been visualized directly and explains the ability of myosin binding to TF at the relaxed conditions. Based on the ratios of nonactivated and activated segments within cTFs, we proposed a mechanism of tropomyosin switching from different states that includes both weakly and strongly bound myosin.


Assuntos
Citoesqueleto de Actina/ultraestrutura , Actinas/ultraestrutura , Subfragmentos de Miosina/ultraestrutura , Tropomiosina/ultraestrutura , Troponina/ultraestrutura , Citoesqueleto de Actina/química , Actinas/química , Animais , Cálcio/metabolismo , Bicamadas Lipídicas/química , Modelos Moleculares , Imagem Molecular , Contração Muscular/genética , Músculo Esquelético/química , Músculo Esquelético/ultraestrutura , Miocárdio/química , Miocárdio/ultraestrutura , Subfragmentos de Miosina/química , Miosinas/química , Ligação Proteica , Coelhos , Sarcômeros/química , Sarcômeros/ultraestrutura , Tropomiosina/química , Troponina/química
7.
Toxins (Basel) ; 11(6)2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146400

RESUMO

Tetrodotoxin (TTX) is an extremely toxic marine compound produced by different genera of bacteria that can reach humans through ingestion mainly of pufferfish but also of other contaminated fish species, marine gastropods or bivalves. TTX blocks voltage-gated sodium channels inhibiting neurotransmission, which in severe cases triggers cardiorespiratory failure. Although TTX has been responsible for many human intoxications limited toxicological data are available. The recent expansion of TTX from Asian to European waters and diversification of TTX-bearing organisms entail an emerging risk of food poisoning. This study is focused on the acute toxicity assessment of TTX administered to mice by oral gavage following macroscopic and microscopic studies. Necropsy revealed that TTX induced stomach swelling 2 h after administration, even though no ultrastructural alterations were further detected. However, transmission electron microscopy images showed an increase of lipid droplets in hepatocytes, swollen mitochondria in spleens, and alterations of rough endoplasmic reticulum in intestines as hallmarks of the cellular damage. These findings suggested that gastrointestinal effects should be considered when evaluating human TTX poisoning.


Assuntos
Neurotoxinas/toxicidade , Tetrodotoxina/toxicidade , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/ultraestrutura , Retículo Endoplasmático Rugoso/efeitos dos fármacos , Feminino , Intestinos/efeitos dos fármacos , Intestinos/patologia , Intestinos/ultraestrutura , Rim/efeitos dos fármacos , Rim/patologia , Rim/ultraestrutura , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/ultraestrutura , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Paralisia/induzido quimicamente , Convulsões/induzido quimicamente , Baço/efeitos dos fármacos , Baço/patologia , Baço/ultraestrutura , Estômago/efeitos dos fármacos , Estômago/ultraestrutura , Testes de Toxicidade Aguda
8.
Biomed Pharmacother ; 117: 109141, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228800

RESUMO

Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) is a flavonoid monomer extracted from its root, which has been used in traditional Chinese medicine, with a long history as a remedy of hypertension and cardiovascular remodeling. The present study was conducted to further investigate the regulatory mechanisms of MHBFC based on the endothelial nitric oxide synthase-nitric oxide (eNOS-NO) signaling pathway. The abdominal aorta of the male Sprague-Dawley rats was narrowed to induce cardiac remodeling, and the rats were given corresponding drugs for 6 weeks after operation. At the end of the experiment, the relevant indexes were detected. The results showed that Nω-nitro-L-arginine methyl ester (L-NAME) could increase the myocardial cell cross-section area, myocardial fibrosis, and the cardiac collagen volume fraction. The serum NO and eNOS levels and the expression of p-eNOS, p-PI3K and p-Akt protein were decreased, and myocardial microvascular endothelial cell (MMVEC) apoptosis increased. However, the above changes were reversed after treatment with MHBFC. These results indicated that MHBFC could increase eNOS protein phosphorylation by increasing PI3K and Akt protein phosphorylation, and activated the eNOS-NO signaling pathway, increased eNOS enzyme activity, catalyzed the generation of protective NO, and counteracted MMVEC apoptosis induced by cardiac remodeling, thereby protecting against myocardial damage and reversing cardiac remodeling.


Assuntos
Chalconas/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/ultraestrutura , Fibrose , Masculino , Microvasos/patologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Óxido Nítrico/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
9.
Zoolog Sci ; 36(2): 112-119, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120645

RESUMO

Cofilin, a member of the ADF/cofilin family, is an actin-binding protein which is widely distributed among eukaryotic organisms and involved in actin filament dynamics in a variety of cell types. In mammalian striated muscles, muscle-type cofilin (MCF or cofilin-2) is predominantly expressed. Previous investigations have shown that MCF plays an essential role in the regulation of assembly of contractile apparatus in skeletal muscle, but its role in cardiac muscle has remained unclear. In the present study, in order to further clarify the role of MCF in organization of myofibrillar structure in vivo, we generated chimeric mice with a combination of MCF-deficient cells that were generated by Cfl2-knockout (Cfl2-/-) and wild type cells containing MCF, and examined the effect of MCF deficiency on striated muscles, especially on the fine structures of contractile apparatus in cardiac muscle. We found that mice chimeric for MCF deficient cells exhibited structural defects in their skeletal muscles as previously reported. Histological analysis showed that MCF deficiency leads to degradation of myofibers and promotion of muscle regeneration. Electron microscopic observation of cardiac muscle of the chimeric mice showed coexistence of the cells with normal sarcomeres and those with disorganized myofibrils in a chimeric pattern. In these cofilin-deficient cells, myofilaments were scattered in the cytoplasm and myofibrillar structures were severely disrupted. These results provide strong evidence for that MCF plays a critical role in the formation and the maintenance of myofibril structure not only in skeletal muscle but also in cardiac muscle.


Assuntos
Cofilina 2/genética , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Actinas/metabolismo , Animais , Quimera , Cofilina 2/metabolismo , Camundongos , Camundongos Knockout , Desenvolvimento Muscular , Músculo Esquelético/patologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Miofibrilas/patologia , Sarcômeros/metabolismo
10.
Nat Commun ; 10(1): 2168, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092830

RESUMO

Adult cardiac tissue undergoes a rapid process of dedifferentiation when cultured outside the body. The in vivo environment, particularly constant electromechanical stimulation, is fundamental to the regulation of cardiac structure and function. We investigated the role of electromechanical stimulation in preventing culture-induced dedifferentiation of adult cardiac tissue using rat, rabbit and human heart failure myocardial slices. Here we report that the application of a preload equivalent to sarcomere length (SL) = 2.2 µm is optimal for the maintenance of rat myocardial slice structural, functional and transcriptional properties at 24 h. Gene sets associated with the preservation of structure and function are activated, while gene sets involved in dedifferentiation are suppressed. The maximum contractility of human heart failure myocardial slices at 24 h is also optimally maintained at SL = 2.2 µm. Rabbit myocardial slices cultured at SL = 2.2 µm remain stable for 5 days. This approach substantially prolongs the culture of adult cardiac tissue in vitro.


Assuntos
Insuficiência Cardíaca/patologia , Coração/fisiologia , Contração Miocárdica/fisiologia , Miocárdio/patologia , Técnicas de Cultura de Tecidos/métodos , Adulto , Animais , Biomimética/métodos , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Miocárdio/citologia , Miocárdio/ultraestrutura , Coelhos , Ratos , Ratos Sprague-Dawley , Sarcômeros/fisiologia
11.
Mol Biol Cell ; 30(14): 1664-1675, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091167

RESUMO

The cardiomyocyte cytoskeleton, including the sarcomeric contractile apparatus, forms a cohesive network with cellular adhesions at the plasma membrane and nuclear--cytoskeletal linkages (LINC complexes) at the nuclear envelope. Human cardiomyopathies are genetically linked to the LINC complex and A-type lamins, but a full understanding of disease etiology in these patients is lacking. Here we show that SUN2-null mice display cardiac hypertrophy coincident with enhanced AKT/MAPK signaling, as has been described previously for mice lacking A-type lamins. Surprisingly, in contrast to lamin A/C-null mice, SUN2-null mice fail to show coincident fibrosis or upregulation of pathological hypertrophy markers. Thus, cardiac hypertrophy is uncoupled from profibrotic signaling in this mouse model, which we tie to a requirement for the LINC complex in productive TGFß signaling. In the absence of SUN2, we detect elevated levels of the integral inner nuclear membrane protein MAN1, an established negative regulator of TGFß signaling, at the nuclear envelope. We suggest that A-type lamins and SUN2 play antagonistic roles in the modulation of profibrotic signaling through opposite effects on MAN1 levels at the nuclear lamina, suggesting a new perspective on disease etiology.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/patologia , Deleção de Genes , Proteínas de Membrana/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Animais , Adesão Celular , Forma do Núcleo Celular , Proteínas de Ligação a DNA/metabolismo , Fibrose , Integrinas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Membrana Nuclear/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sarcômeros/metabolismo , Sarcômeros/ultraestrutura , Proteínas de Ligação a Telômeros/deficiência , Fator de Crescimento Transformador beta/metabolismo
12.
Environ Toxicol ; 34(7): 878-885, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31037826

RESUMO

Perfluorooctanoic acid (PFOA) is an octanoic acid and is found in wildlife and humans. We have investigated mitochondrial toxicity in isolated mitochondria from, placenta, brain, liver, and heart after oral exposure with PFOA in mice during gestational days (7-15). Histopathological examination and mitochondrial toxicity parameters were assayed. Results indicated that PFOA decreased the weight of the fetus and placenta, the length of the fetus and the diameter of the placenta, dead fetuses and dead macerated fetuses in treated mice with 25 mg/kg. Histopathological examination showed that PFOA induced pathological abnormalities in liver, brain, heart, and placenta. Also, PFOA induced mitochondria toxicity in brain, liver, heart of mouse fetus. Our results indicate that PFOA up to 20 mg/kg exposure adversely affect embryofetal/developmental because for mitochondria dysfunction. These results suggested that mitochondrial dysfunction induced by PFOA in liver, heart, and brain lead to developmental toxicity and abnormality in tissues.


Assuntos
Aborto Espontâneo/induzido quimicamente , Caprilatos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Feto/efeitos dos fármacos , Fluorcarbonetos/toxicidade , Exposição Materna/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/ultraestrutura , Feminino , Feto/metabolismo , Feto/patologia , Coração/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/ultraestrutura , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/fisiologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/fisiologia , Miocárdio/ultraestrutura , Gravidez
13.
Acta Histochem ; 121(5): 553-562, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31068261

RESUMO

Cisplatin is a powerful chemotherapeutic agent. Cardiotoxicity is one of its major adverse effects. Ginger is a commonly used element in herbal medicine due to its anti-oxidant potentials. This study was planned to assess the histological changes induced by cisplatin in the cardiac muscle and to clarify the possible protective influence of ginger intake. Forty rats were divided into four groups. Control; given normal saline. Ginger; received oral ginger (500 mg/kg/day) for 12 days. Cisplatin; given cisplatin (2 mg/kg/day) daily by intraperitoneal injection for 1 week. Cisplatin + Ginger; received ginger (500 mg/kg/day) for 5 days prior to and concomitant with intraperitoneal injection of cisplatin (2 mg/kg/day) for 1 week. Serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were estimated. Cardiac specimens were subjected to light, electron microscopic and immunohistochemical study using anti-P53 and anti-TNF-α antibodies. Morphometric and statistical studies were done. In Cisplatin group, cardiac muscle fibers appeared disorganized, disrupted or degenerated with pyknotic nuclei and showed a significant rise in the number of anti-P53 positive nuclei. Significant increments in the percent area of collagenous fibers and TNF-α immune-expression were observed. Ultrastructurally, the cardiomyocytes displayed disorganized or interrupted myofibrils, swollen disrupted mitochondria, and widening of intercalated discs. Serum levels of CK and LDH were significantly elevated. Cisplatin + Ginger group showed marked improvement in the cardiac histology and ultrastructure, downregulation of P53 and TNF-α immune-expressions and reduction in CK and LDH serum levels. In conclusion, ginger exhibits a protective effect against cisplatin cardiotoxicity mostly through its anti-apoptotic, anti-oxidant and anti-inflammatory properties.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxicidade/tratamento farmacológico , Cisplatino/toxicidade , Gengibre , Coração/efeitos dos fármacos , Miocárdio/patologia , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Creatina Quinase/sangue , Imuno-Histoquímica , L-Lactato Desidrogenase/sangue , Microscopia , Microscopia Eletrônica , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Ratos
14.
NMR Biomed ; 32(6): e4091, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30968985

RESUMO

Mitochondrial dysfunction is considered to be an important component of many metabolic diseases yet there is no reliable imaging biomarker for monitoring mitochondrial damage in vivo. A large prior literature on inter-conversion of ß-hydroxybutyrate and acetoacetate indicates that the process is mitochondrial and that the ratio reflects a specifically mitochondrial redox state. Therefore, the conversion of [1,3-13 C]acetoacetate to [1,3-13 C]ß-hydroxybutyrate is expected to be sensitive to the abnormal redox state present in dysfunctional mitochondria. In this study, we examined the conversion of hyperpolarized (HP) 13 C-acetoacetate (AcAc) to 13 C-ß-hydroxybutyrate (ß-HB) as a potential imaging biomarker for mitochondrial redox and dysfunction in perfused rat hearts. Conversion of HP-AcAc to ß-HB was investigated using 13 C magnetic resonance spectroscopy in Langendorff-perfused rat hearts in four groups: control, global ischemic reperfusion, low-flow ischemic, and rotenone (mitochondrial complex-I inhibitor)-treated hearts. We observed that more ß-HB was produced from AcAc in ischemic hearts and the hearts exposed to complex I inhibitor rotenone compared with controls, consistent with the accumulation of excess mitochondrial NADH. The increase in ß-HB, as detected by 13 C MRS, was validated by a direct measure of tissue ß-HB by 1 H nuclear magnetic resonance in tissue extracts. The redox ratio, NAD+ /NADH, measured by enzyme assays of homogenized tissue, also paralleled production of ß-HB from AcAc. Transmission electron microscopy of tissues provided direct evidence for abnormal mitochondrial structure in each ischemic tissue model. The results suggest that conversion of HP-AcAc to HP-ß-HB detected by 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Isótopos de Carbono/metabolismo , Coração/fisiopatologia , Espectroscopia de Ressonância Magnética , Mitocôndrias/metabolismo , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Congelamento , Hemodinâmica , Masculino , Mitocôndrias/ultraestrutura , Miocárdio/metabolismo , Miocárdio/ultraestrutura , NAD/metabolismo , Oxirredução , Perfusão , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley
15.
J Physiol Pharmacol ; 70(1)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31019122

RESUMO

The influence of low-energy defibrillation on changes in the ET-1 levels in the myocardium and on disruptions in coronary blood flow and microcirculation being their consequence still remains unclear. Myocardial microcirculatory dysfunction is considered as a significant cause underlying myocardial dysfunction in post-cardiac arrest syndrome. This study is aimed at evaluating time-dependent changes in ET-1 levels in serum and the heart of a healthy rabbit following the application of a low-energy two-phase shock impulse. The research was conducted in 35 healthy rabbits at the age of 36 - 42 weeks and with body mass from 3200 to 4150 grams. The animals were divided in a randomized way into four groups depending on the dose of the electrical energy planned for the application during the experiment. The life parameters of the animals were monitored with the application of BeneView T5 patient monitor. The concentration of endothelin-1 in the groups was measured before, 15 and 360 minutes after the application of the low-energy double-phase straight-lined electrical impulse. A transthoracic low-energy defibrillation shock impulse causes a long-term increase in the endothelin-1 levels in the heart muscle and blood serum in a healthy rabbit. The increase in ET-1 levels results from the effect of electrical energy, independently of consequences of the ischemia/reperfusion injury. The increase in the endothelin-1 levels may lead to capillary blood flow abnormalities in the heart, contributing to the development of its dysfunction in the course of postresuscitation disease.


Assuntos
Estimulação Elétrica , Endotelina-1/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Animais , Pressão Sanguínea , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Ventrículos do Coração/ultraestrutura , Masculino , Miocárdio/ultraestrutura , Coelhos , Tirosina/análogos & derivados , Tirosina/metabolismo , Função Ventricular
16.
Nat Commun ; 10(1): 1269, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894521

RESUMO

Systemic light chain amyloidosis (AL)  is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-ß architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (Vl) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic Vl, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.


Assuntos
Amiloide/ultraestrutura , Cadeias Leves de Imunoglobulina/ultraestrutura , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Miocárdio/ultraestrutura , Agregação Patológica de Proteínas/patologia , Idoso , Sequência de Aminoácidos , Amiloide/imunologia , Amiloide/metabolismo , Autopsia , Microscopia Crioeletrônica , Humanos , Cadeias Leves de Imunoglobulina/imunologia , Cadeias Leves de Imunoglobulina/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/imunologia , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Masculino , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Agregação Patológica de Proteínas/diagnóstico , Agregação Patológica de Proteínas/imunologia , Agregação Patológica de Proteínas/metabolismo , Conformação Proteica em Folha beta , Dobramento de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Índice de Gravidade de Doença
17.
Nat Commun ; 10(1): 1103, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894526

RESUMO

Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.


Assuntos
Amiloide/ultraestrutura , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Sequência de Aminoácidos , Amiloide/química , Amiloide/genética , Microscopia Crioeletrônica , Humanos , Cadeias Leves de Imunoglobulina/química , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/ultraestrutura , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Modelos Moleculares , Mutação , Miocárdio/química , Miocárdio/imunologia , Miocárdio/ultraestrutura , Conformação Proteica , Dobramento de Proteína
18.
Biosci Rep ; 39(4)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30923227

RESUMO

Cannabinoid receptor 2 (CB2R) has been reported to play an important role in the regulation of pathogenesis and progression of myocardial infarction (MI). Here we tried to investigate its potential mechanisms. The ratio of infarct size in heart issue was detected by TTC staining, and cardiac functions were calculated according to echocardiographic evaluation. Cell viability in cardiomyocytes was investigated by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. Western blot was used to detect autophagy-related proteins including Beclin-1, LC3, p62, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of rapamycin rabbit (mTOR)-p70 ribosomal protein S6 kinase (p70S6K) signaling-related proteins including AMPK, mTOR, p70S6K, and their phosphorylation formation. Rapamycin was used for the induction of autophagy. Cleaved caspase-3 and Bax were detected for analyzing apoptosis. TEM was used for the detection of autophagosomes. We found that CB2R deletion (CB2R KO) largely deteriorated the severity of MI and the cardiac function as well as cell viability of cardiomyocytes. Knocking out CB2R decreased the level of autophagy in heart issues from MI mice as well as cardiomyocytes under oxygen-glucose deprivation (OGD). Furthermore, CB2R dysfunction significantly attenuated the cardiac protective effects of rapamycin both in vivo and in vitro Finally, we found that CB2R-mediated autophagy was induced by AMPK-mTOR-p70S6K signaling pathway. Our current study demonstrated for the first time that CB2R deletion led to a detrimental effect of MI through the dysfunction of AMPK-mTOR-p70S6K signaling pathway, which might provide a novel insight in the treatment of MI.


Assuntos
Autofagia/genética , Infarto do Miocárdio/genética , Miocárdio/metabolismo , Receptor CB2 de Canabinoide/genética , Animais , Apoptose/genética , Sobrevivência Celular/genética , Modelos Animais de Doenças , Ecocardiografia , Deleção de Genes , Humanos , Camundongos , Camundongos Knockout , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cultura Primária de Células , Proteínas Quinases/genética , Coelhos , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
19.
Int J Mol Med ; 43(4): 1575-1584, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816437

RESUMO

Acute pulmonary embolism (APE) with cardiac arrest (CA) is associated with a high mortality rate. Even upon return of the spontaneous circulation (ROSC), APE­CA survivors are prone to myocardial cell apoptosis, a key cellular mechanism that induces heart failure. A recent study by our group discovered a post­resuscitation imbalance in the serum angiotensin­converting enzyme (ACE)2/ACE axis of the renin­angiotensin system (RAS), as well as regressive cardiac function in a porcine model of APE­CA. However, it has remained elusive how this imbalance in the ACE2/ACE axis affects myocardial cell apoptosis. In the present study, western blot and immunohistochemical analyses demonstrated that the RAS was only activated in the left myocardium, as evidenced by a decreased ACE2/ACE ratio following APE­CA and ROSC, but not the right myocardium. Ultrastructural analysis confirmed myocardial apoptosis in the left and right myocardium. Furthermore, B­cell lymphoma 2 (Bcl­2)­associated X protein (Bax) and caspase­3 levels were elevated and Bcl­2 levels were decreased in the left myocardium following APE­CA and ROSC. Treatment with the ACE inhibitor captopril for 30 min after initiation of ROSC prevented the increase in Bax and the decrease in Bcl­2 in the left myocardium compared with that in saline­treated pigs. Captopril also inhibited the activation of extracellular signal­regulated kinase (ERK)1/2 in the left myocardium. The results of the present study suggest that an imbalance in the ACE2/ACE axis has an important role in myocardial apoptosis following APE­CA, which may be attributed to decreased ERK1/2 activation. In addition, it was indicated that captopril prevents apoptosis in the left myocardium after ROSC.


Assuntos
Apoptose , Parada Cardíaca/enzimologia , Parada Cardíaca/etiologia , Miocárdio/enzimologia , Miocárdio/patologia , Peptidil Dipeptidase A/metabolismo , Embolia Pulmonar/complicações , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Captopril/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Miocárdio/ultraestrutura , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suínos
20.
J Card Fail ; 25(4): 286-300, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769036

RESUMO

BACKGROUND: The (pro)renin receptor [(P)RR)] is involved in the activation of local renin-angiotensin system and subsequent development of cardiovascular disease. We investigated the therapeutic effect of a (P)RR blocker, handle-region peptide (HRP), on chronic kidney disease (CKD)-associated heart failure. METHODS AND RESULTS: CKD was induced in C57BL/6J mice by means of five-sixths nephrectomy. Eight weeks later, cardiac dysfunction and cardiac dilatation with hypertension developed. Mice were then assigned to 1 of the 3 following groups: vehicle, low-dose (0.01 mg·kg-1·d-1) HRP, or high-dose (0.3 mg·kg-1·d-1) HRP for 4 weeks. High-dose HRP treatment reversed left ventricular dilation and significantly improved cardiac dysfunction with ameliorated hypertension compared with the vehicle. The hearts with high-dose HRP treatment showed significant attenuation of cardiac fibrosis, cardiomyocyte hypertrophy, macrophage infiltration, and oxidative DNA damage. This treatment decreased the myocardial expressions of angiotensin (Ang) II, Ang II type 1 receptor, transforming growth factor ß1, extracellular matrix-related proteins, and lipid peroxidation. Autophagy was activated in the cardiomyocyte from nephrectomized mice, but HRP treatment had no effect on cardiomyocyte autophagy. CONCLUSIONS: This study indicates that (P)PR blockade is a beneficial strategy by suppressing cardiac fibrosis and hypertrophy to ameliorate heart failure caused by CKD.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Oligopeptídeos/administração & dosagem , Receptores de Superfície Celular/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Animais , Western Blotting , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Miocárdio/ultraestrutura , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo
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