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1.
Life Sci ; 283: 119866, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352257

RESUMO

AIMS: Morphine, a commonly used drug for anesthesia, affects lipid metabolism in different tissues, but the mechanism is currently unclear. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme responsible for the first step of triglyceride (TG) hydrolysis. Here we aim to investigate whether ATGL phosphorylation is involved in morphine-induced TG accumulation. MAIN METHODS: Oil red O staining and TG content analysis were used to detect the effect of morphine on lipid storage. A series of ATGL phosphoamino acid site mutant plasmids were constructed by gene synthesis and transfected to HL-1 cells to evaluate the phosphorylation levels of ATGL phosphoamino acid in morphine-treated HL-1 cells with immunoprecipitation and immunoblotting assay. KEY FINDINGS: Morphine acute treatment induced excessive accumulation of TG and decreased the phosphorylation level of ATGL Ser406 in HL-1 cells. Of note, the phosphorylation positive mutation of ATGL Ser406 to aspartic acid effectively reversed morphine-induced excessive accumulation of TG in HL-1 cells. SIGNIFICANCE: This discovery will help to fully understand the lipid regulation function of morphine in a new scope. In addition, it will expand the phosphorylation research of ATGL more comprehensively and provide powerful clues for lipid metabolism regulation.


Assuntos
Lipase/metabolismo , Morfina/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Masculino , Camundongos , Morfina/farmacocinética , Miocárdio/patologia , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos
2.
Cell Death Dis ; 10(9): 670, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511493

RESUMO

Transforming growth factor (TGF)-ß1, a main profibrogenic cytokine in the progression of idiopathic pulmonary fibrosis (IPF), induces differentiation of pulmonary fibroblasts to myofibroblasts that produce high levels of collagen, leading to concomitantly loss of lung elasticity and function. Recent studies implicate the importance of microRNAs (miRNAs) in IPF but their regulation and individual pathological roles remain largely unknown. We used both RNA sequencing and quantitative RT-PCR strategies to systematically study TGF-ß1-induced alternations of miRNAs in human lung fibroblasts (HFL). Our data show that miR-133a was significantly upregulated by TGF-ß1 in a time- and concentration-dependent manner. Surprisingly, miR-133a inhibits TGF-ß1-induced myofibroblast differentiation whereas miR-133a inhibitor enhances TGF-ß1-induced myofibroblast differentiation. Interestingly, quantitative proteomics analysis indicates that miR-133a attenuates myofibroblast differentiation via targeting multiple components of TGF-ß1 profibrogenic pathways. Western blot analysis confirmed that miR-133a down-regulates TGF-ß1-induced expression of classic myofibroblast differentiation markers such as ɑ-smooth muscle actin (ɑ-SMA), connective tissue growth factor (CTGF) and collagens. miRNA Target Searcher analysis and luciferase reporter assays indicate that TGF-ß receptor 1, CTGF and collagen type 1-alpha1 (Col1a1) are direct targets of miR-133a. More importantly, miR-133a gene transferred into lung tissues ameliorated bleomycin-induced pulmonary fibrosis in mice. Together, our study identified TGF-ß1-induced miR-133a as an anti-fibrotic factor. It functions as a feed-back negative regulator of TGF-ß1 profibrogenic pathways. Thus, manipulations of miR-133a expression may provide a new therapeutic strategy to halt and perhaps even partially reverse the progression of IPF.


Assuntos
Diferenciação Celular/genética , Fibrose Pulmonar Idiopática/metabolismo , MicroRNAs/metabolismo , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Actinas/genética , Actinas/metabolismo , Animais , Bleomicina/toxicidade , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Feminino , Células HEK293 , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miofibroblastos/efeitos dos fármacos , Células NIH 3T3 , Proteômica , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Vascul Pharmacol ; 96-98: 26-32, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28797762

RESUMO

Ceramide accumulation in blood vessels has been attributed to vascular dysfunction in progressive vascular complications in metabolic diseases. The present study showed that ceramide pretreatment promoted PE-induced vasoconstriction in rat endothelium-denuded vascular rings in a time- and dose-dependent manner. Endoplasmic reticulum (ER) stress inhibitors, 4-PBA and TUDCA, COX-2 inhibitors, Celecoxib and NS398, as well as PGE2 receptor antagonist AH-6809 attenuated ceramide-promoted vascular hyperreactivity. Ceramide promoted the transcriptional and translational expression of COX-2 and BiP in VSMCs, which were blocked by the ER stress inhibitors, 4-PBA and TUDCA. These findings show that ceramide enhances PE-induced vascular smooth muscle constriction by mediation of the ER stress/COX-2/PGE2 pathway. Therapeutic strategies targeted to reducing ER stress and COX-2 activation might be beneficial in attenuating vascular complications. CHEMICAL COMPOUNDS: C2-Ceramide (N-acetyl-d-erythro-sphingosine) CID:2662 Tauroursodeoxycholic Acid Sodium (TUDCA) CID:9848818 phenylephrine (PE) CID:6041.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Esfingosina/análogos & derivados , Vasoconstrição/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Linhagem Celular , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Técnicas In Vitro , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia , Fatores de Tempo , Transfecção , Regulação para Cima
4.
Sci Rep ; 6: 19782, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26795240

RESUMO

Excessive retention of neutral lipids in cardiac lipid droplets (LDs) is a common observation in cardiomyopathy. Thus, the systematic investigation of the cardiac LD proteome will help to dissect the underlying mechanisms linking cardiac steatosis and myocardial dysfunction. Here, after isolation of LDs from normal and dysfunctional Sprague-Dawley rat hearts, we identified 752 heart-associated LD proteins using iTRAQ quantitative proteomic method, including 451 proteins previously unreported on LDs. The most noteworthy finding was the identification of the membrane resealing protein, dysferlin. An analysis of dysferlin truncation mutants indicated that its C2 domain was responsible for its LD localization. Quantitative proteomic results further determined that 27 proteins were increased and 16 proteins were decreased in LDs from post pressure overload-induced dysfunctional hearts, compared with normal hearts. Notably, adipose triacylglycerol lipase (ATGL) was dramatically decreased and dysferlin was substantially increased on dysfunctional cardiac LDs. This study for the first time reveals the dataset of the heart LD proteome in healthy tissue and the variation of it under cardiac dysfunction. These findings highlight an association between the altered LD protein localization of dysferlin and ATGL and myocardial dysfunction.


Assuntos
Coração/fisiologia , Lipase/metabolismo , Gotículas Lipídicas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Pressão , Proteômica/métodos , Animais , Coração/fisiopatologia , Espectrometria de Massas , Proteínas de Membrana/química , Proteínas Musculares/química , Miocárdio/metabolismo , Ligação Proteica , Domínios Proteicos , Mapas de Interação de Proteínas , Proteoma/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Frações Subcelulares/metabolismo , Triglicerídeos/metabolismo
5.
Sci Rep ; 5: 12070, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26159641

RESUMO

Testicular Leydig cells contain abundant cytoplasmic lipid droplets (LDs) as a cholesteryl-ester store for releasing cholesterols as the precursor substrate for testosterone biosynthesis. Here, we identified the protein composition of testicular LDs purified from adult mice by using mass spectrometry and immunodetection. Among 337 proteins identified, 144 were previously detected in LD proteomes; 44 were confirmed by microscopy. Testicular LDs contained multiple Rab GTPases, chaperones, and proteins involved in glucuronidation, ubiquination and transport, many known to modulate LD formation and LD-related cellular functions. In particular, testicular LDs contained many members of both the perilipin family and classical lipase/esterase superfamily assembled predominately in adipocyte LDs. Thus, testicular LDs might be regulated similar to adipocyte LDs. Remarkably, testicular LDs contained a large number of classical enzymes for biosynthesis and metabolism of cholesterol and hormonal steroids, so steroidogenic reactions might occur on testicular LDs or the steroidogenic enzymes and products could be transferred through testicular LDs. These characteristics differ from the LDs in most other types of cells, so testicular LDs could be an active organelle functionally involved in steroidogenesis.


Assuntos
Células Intersticiais do Testículo/metabolismo , Gotículas Lipídicas/metabolismo , Proteoma/metabolismo , Animais , Proteínas de Transporte/metabolismo , Esterases/metabolismo , Lipase/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perilipina-1 , Fosfoproteínas/metabolismo , Proteômica/métodos , Esteroides/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
6.
Biochim Biophys Acta ; 1853(5): 918-28, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25655664

RESUMO

Brown adipose tissue (BAT) maintains animal body temperature by non-shivering thermogenesis, which is through uncoupling protein 1 (UCP1) that uncouples oxidative phosphorylation and utilizes ß-oxidation of fatty acids released from triacylglycerol (TAG) in lipid droplets (LDs). Increasing BAT activity and "browning" other tissues such as white adipose tissue (WAT) can enhance the expenditure of excess stored energy, and in turn reduce prevalence of metabolic diseases. Although many studies have characterized the biology of BAT and brown adipocytes, BAT LDs especially their activation induced by cold exposure remain to be explored. We have isolated LDs from mouse interscapular BAT and characterized the full proteome using mass spectrometry. Both morphological and biochemical experiments showed that the LDs could tightly associate with mitochondria. Under cold treatment mouse BAT started expressing LD structure protein PLIN-2/ADRP and increased expression of PLIN1. Both hormone sensitive lipase (HSL) and adipose TAG lipase (ATGL) were increased in LDs. In addition, isolated BAT LDs showed increased levels of the mitochondrial protein UCP1, and prolonged cold exposure could stimulate BAT mitochondrial cristae biogenesis. These changes were in agreement with the data from transcriptional analysis. Our results provide the BAT LD proteome for the first time and show that BAT LDs facilitate heat production by coupling increasing TAG hydrolysis through recruitment of ATGL and HSL to the organelle and expression of another LD resident protein PLIN2/ADRP, as well as by tightly associating with activated mitochondria. These findings will benefit the study of BAT activation and the interaction between LDs and mitochondria.


Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Gotículas Lipídicas/metabolismo , Mitocôndrias/metabolismo , Tecido Adiposo Marrom/ultraestrutura , Animais , Metabolismo Energético , Gotículas Lipídicas/ultraestrutura , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Mapas de Interação de Proteínas , Proteômica
7.
Proc Natl Acad Sci U S A ; 111(31): 11437-42, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-25028495

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17ß-hydroxysteroid dehydrogenase-13 (17ß-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17ß-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17ß-HSD family plays an important role in lipid metabolism, 17ß-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17ß-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17ß-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17ß-HSD13 as a pathogenic protein in the development of NAFLD.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Proteômica/métodos , Animais , Células Cultivadas , Dieta Hiperlipídica , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Lipídeos/química , Lipogênese , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Proteoma/metabolismo , Reprodutibilidade dos Testes , Regulação para Cima
8.
J Proteome Res ; 10(10): 4757-68, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21870882

RESUMO

The lipid droplet (LD) is a universal organelle governing the storage and turnover of neutral lipids. Mounting evidence indicates that elevated intramuscular triglyceride (IMTG) in skeletal muscle LDs is closely associated with insulin resistance and Type 2 Diabetes Mellitus (T2DM). Therefore, the identification of the skeletal muscle LD proteome will provide some clues to dissect the mechanism connecting IMTG with T2DM. In the present work, we identified 324 LD-associated proteins in mouse skeletal muscle LDs through mass spectrometry analysis. Besides lipid metabolism and membrane traffic proteins, a remarkable number of mitochondrial proteins were observed in the skeletal muscle LD proteome. Furthermore, imaging by fluorescence microscopy and transmission electronic microscopy (TEM) directly demonstrated that mitochondria closely adhere to LDs in vivo. Moreover, our results revealed for the first time that apolipoprotein A-I (apo A-I), the principal apolipoprotein of high density lipoprotein (HDL) particles, was also localized on skeletal muscle LDs. Further studies verified that apo A-I was expressed endogenously by skeletal muscle cells. In conclusion, we report the protein composition and characterization of skeletal muscle LDs and describe a novel LD-associated protein, apo A-I.


Assuntos
Apolipoproteína A-I/metabolismo , Lipídeos/química , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Proteômica/métodos , Adolescente , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Resistência à Insulina , Lipoproteínas HDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão/métodos , Microscopia de Fluorescência/métodos , Modelos Biológicos
9.
Endocrinology ; 152(6): 2206-18, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21505048

RESUMO

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. (3)H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Ácido Oleico/metabolismo , Estresse Oxidativo , Palmitatos/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Regulação para Baixo , Humanos , Insulina/metabolismo , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
J Lipid Res ; 52(7): 1319-27, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21518696

RESUMO

Chronic exposure to saturated fatty acids can cause insulin resistance. However, the acute effects of fatty acids are not clear and need to be elucidated because plasma fatty acid concentrations fluctuate postprandially. Here, we present the acute effects of palmitate (PA) on skeletal muscle cells and their underlying molecular mechanisms. Immuno-fluorescence results showed that PA rapidly induced GLUT4 translocation and stimulated glucose uptake in rat skeletal muscle cell line L6. Phosphorylation of AMP-activated protein kinase (AMPK), Akt, and extracellular signal-related kinase1/2 (ERK1/2) was enhanced by PA in a time-dependent manner. Cell surface-bound PA was sufficient to stimulate Akt phosphorylation. The inhibitors of PI3 kinase (PI3K), AMPK, Akt, and ERK1/2 could decrease PA-induced glucose uptake, and PI3K inhibitor decreased AMPK, Akt, and ERK1/2 phosphorylation. Weakening AMPK activity reduced phosphorylation of Akt but not ERK1/2, and Akt inhibitor could not affect ERK1/2 activation either. Meanwhile, ERK1/2 inhibitors had no effect on Akt phosphorylation. Taken together, our data suggest that PA-mediated glucose uptake in skeletal muscle cells may be stimulated by the binding of PA to cell surface and followed by PI3K/AMPK/Akt and PI3K/ERK1/2 pathways independently.


Assuntos
Glucose/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Ácido Palmítico/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ativação Enzimática/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
11.
J Surg Res ; 169(2): 179-87, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20189584

RESUMO

BACKGROUND: Adenosine monophosphate-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischemic injury and apoptosis. Recent progress shed light on various factors, including adiponectin, MIF, H11K, and metformin in the activation of AMPK. It is uncertain whether the activation of AMPK is contributed to cardioprotection of opioids. Here we show that morphine, an exogenous non-peptide opioid receptor agonist, can modulate the activation of the cardioprotective AMPK pathway during ischemia and exert anti-apoptotic effects through AMPK. METHODS: Isolated rat hearts were perfused on a constant pressure Langendorff system and subjected to 30 min of global ischemia followed by 60 min of reperfusion. The hearts received vehicles, morphine, a combination of morphine and compound C, a combination of morphine and STO609, a combination of morphine and BAPTA-AM at the onset of ischemia. Hemodynamics parameters, infarct size, release of intracellular creatine kinase, expression of AMPK, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining were analyzed. RESULTS: Morphine significantly increased phosphorylation level of Thr172 site on AMPK, left ventricular function, and reduced infarct size as a percentage of the area at risk (IS/AAR from 63% ± 7% to 40% ± 5%), release of intracellular creatine kinase (from 319 ± 46 to 156 ± 42IU/60 min/gdw), apoptosis ratio (from 16% ± 2% to 5% ± 1.4%) during reperfusion in comparison with the control group. A inhibitor of AMPK, compound C abrogated phosphorylation of AMPK induced by morphine, the improvement in myocardial function, and the reduction of IS/AAR (58% ± 6%), release of intracellular creatine kinase (270 ± 40IU/60 min/gdw), apoptosis ratio (13% ± 1.5%). A Ca(2+)/calmodulin-dependent protein kinase kinase inhibitor STO609 and a chelator of intracellular Ca(2+) stores BAPTA-AM also abolished the cardioprotection of morphine. CONCLUSIONS: Morphine can ameliorate myocardial contractile dysfunction and limit infarct size following ischemia and reperfusion by a mechanism involving activation of AMPK, and activate AMPK by Ca(2+)-CaMKKß-dependent phosphorylation.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/fisiologia , Analgésicos Opioides/farmacologia , Precondicionamento Isquêmico Miocárdico/métodos , Morfina/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cálcio/fisiologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/fisiologia , Masculino , Modelos Animais , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fosforilação/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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