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1.
PLoS One ; 15(5): e0232374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365085

RESUMO

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-to-human porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF.


Assuntos
Fibrilação Atrial/fisiopatologia , Insuficiência Cardíaca/complicações , Traumatismo por Reperfusão Miocárdica/complicações , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/patologia , Angiografia Coronária , Modelos Animais de Doenças , Eletrocardiografia , Insuficiência Cardíaca/fisiopatologia , Humanos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Volume Sistólico , Suínos
2.
Microvasc Res ; 130: 104009, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333940

RESUMO

AIMS: The purpose of the present study was to investigate the possible role of TIPE2 on acute lung injury (ALI) induced by myocardial ischemia/reperfusion (MIR) in diabetic rats. METHODS: Sprague-Dawley (SD) rats were randomly separated into four groups: control+sham (C + sham); control+MIR (C + MIR); diabetes+sham (D + sham); diabetes+MIR (D + MIR). Diabetes was induced using streptozotocin. Eight weeks after diabetes induction, MIR was conducted. At 2 h after MIR, myocardial injury indices were assessed; arterial blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for corresponding detection. RESULTS: Rats subjected to MIR showed serious ALI (estimated via pathological changes, lung injury score and Wet/Dry weight ratio), lung inflammation and pulmonary cell apoptosis compared with sham groups, especially in D + MIR group. Evaluation of protein expression in lung tissues showed that p-JNK and nuclear NF-κB p65 protein levels were higher in D + MIR group as compared with C + MIR group. Besides, either hyperglycemia or MIR can significantly upregulate TIPE2 protein levels. CONCLUSIONS: In conclusion, diabetic lungs are more susceptible to MIR. TIPE2 may involve in this pathological process, possibly through regulation of inflammation, oxidative stress and apoptosis.


Assuntos
Lesão Pulmonar Aguda/etiologia , Diabetes Mellitus Experimental/complicações , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/metabolismo , Traumatismo por Reperfusão Miocárdica/complicações , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Apoptose , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina , Fator de Transcrição RelA/metabolismo
3.
Mol Med Rep ; 21(2): 641-648, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974615

RESUMO

Crocetin, a natural compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. Previous studies demonstrated that crocetin reduced ischemia/reperfusion (I/R) injury by attenuating cytotoxicity and cellular apoptosis. However, the previous mechanistic studies did not fully elucidate its pharmacological effects on cardiac damage, especially I/R injury. The present study verified its cardioprotective effects in a Langendorff perfusion system, an ex vivo model of I/R. It was demonstrated that crocetin significantly attenuated the activities of pro­inflammatory cytokines and nuclear factor erythroid­2 related factor 2 (Nrf2)/heme oxygenase­1 signaling. The present study provided novel insight that crocetin regulated the unfolded protein response (UPR) and decreased associated protein levels to protect the heart. Furthermore, it was identified that Nrf2 played a key role in the cardioprotective effect of crocetin by attenuating inflammation and the UPR.


Assuntos
Carotenoides/uso terapêutico , Inflamação/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Resposta a Proteínas não Dobradas , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Carotenoides/farmacologia , Linhagem Celular , Inflamação/complicações , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Miocárdio/enzimologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Perfusão , Ratos Sprague-Dawley , Transdução de Sinais , Resposta a Proteínas não Dobradas/efeitos dos fármacos
4.
Eur J Pharmacol ; 866: 172796, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738932

RESUMO

Diabetic patients are sensitive to myocardial ischemia-reperfusion (MI/R) injury. During diabetes, branched-chain amino acid (BCAA) catabolism is defective and mitochondrial phosphatase 2C (PP2Cm) expression is reduced. This study aims to elucidate the relationship between PP2Cm downregulation and BCAA catabolism defect in diabetic mice against MI/R injury. PP2Cm was significantly downregulated in hearts of diabetic mice. The cardiac function was improved and the myocardial infarct size and apoptosis were decreased in diabetic mice overexpressing PP2Cm after MI/R. In diabetic mice, the cardiac BCAA and its metabolites branched-chain keto-acids (BCKA) levels, and p-BCKDE1α (E1 subunit of BCKA dehydrogenase)/BCKDE1α ratio were increased while the BCKD activity was decreased. Treatment of diabetic mice subjected to MI/R injury with BT2, a BCKD kinase (BDK) inhibitor, alleviated the BCAA catabolism defect, and improved the cardiac function alongside reduced apoptosis. PP2Cm overexpression alleviated the BCAA catabolism defect and MI/R injury. Similarly, MnTBAP ameliorated the oxidative stress and MI/R injury. BCKA treatment of H9C2 cells under simulated ischemia/reperfusion (SI/R) injury significantly decreased cell viability and increased LDH release and apoptosis. These effects were alleviated by BT2 and MnTBAP treatments. These results suggested that PP2Cm directly mediates the BCAA catabolism defect and oxidative stress observed after MI/R in diabetes. Overexpression of PP2Cm alleviates MI/R injury by reducing the catabolism of BCAA and oxidative stress.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Diabetes Mellitus Experimental/complicações , Regulação Enzimológica da Expressão Gênica , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo/genética , Proteína Fosfatase 2C/genética , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/complicações
5.
J Diabetes Res ; 2019: 7869318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886285

RESUMO

Objective: With the increasing incidence of diabetes mellitus (DM) combined with myocardial ischemia, how to reduce myocardial ischemia-reperfusion injury in DM patients has become a major problem faced by clinicians. We investigated the therapeutic effects of dexmedetomidine (DEX) on myocardial ischemia-reperfusion injury in DM rats and its effect on endoplasmic reticulum stress. Methods: SD rats with SPF grade were randomly divided into 6 groups: non-DM rats were divided into the sham operation group (NDM-S group), ischemia-reperfusion group (NDM-IR group), and dexmedetomidine group (NDM-DEX group); DM rats were divided into the diabetic sham operation group (DM-S group), diabetes-reperfusion group (DM-IR group), and diabetes-dexmedetomidine (DM-DEX) group, with 10 rats in each group. Then the effects of DEX on the changes of CK-MB and cTnT levels were examined. The effects of myocardial pathological damage and myocardial infarct size were detected. The apoptosis of cardiomyocytes was detected. The apoptosis of heart tissue cells was also tested through the expressions of cleaved caspase-3, Bcl-2, and Bax proteins. The expression of endoplasmic reticulum stress-related proteins GRP78, CHOP, ERO1α, ERO1ß, and PDI was examined. The hypoxia/reoxygenation (H/R) injury cell model was established, the effects of DEX, DEX+ ERS agonist on cell apoptosis was also detected. Results: The myocardial damage of DM-IR was more severe than that of NDM-IR rats. DEX could reduce the expression of CK-MB and cTnT, reduce pathological damage, and reduce scar formation and improve fibrosis. DEX can reduce the expression of GRP78, CHOP, ERO1α, ERO1ß, and PDI proteins in vivo and in vitro. And the effect of DEX on cell apoptosis could be blocked by ERS agonist. Conclusion: DEX attenuates myocardial ischemia-reperfusion injury in DM rats and H/R injury cell, which is associated with the reduction of ERS-induced cardiomyocyte apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Dexmedetomidina/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Linhagem Celular , Creatina Quinase Forma MB/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fibrose , Proteínas de Choque Térmico/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Transcrição CHOP/metabolismo , Troponina T/sangue
6.
Int J Mol Sci ; 20(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766239

RESUMO

We have evidence that the intravenous infusion of sodium nitrite (NaNO2) results in an antiarrhythmic effect when given 24 h prior to an ischemia and reperfusion (I/R) insult in anaesthetized dogs. This protection was associated with the reduction of reactive oxygen species resulting from I/R through the attenuation of mitochondrial respiration. Here, we examined whether the changes in calcium, which also contributes to arrhythmia generation, play a role in the NaNO2-induced effect. On the first day, 30 anaesthetized dogs were treated either with saline or NaNO2 (0.2 µmol/kg/min) for 20 min. Some animals were subjected to a 25 min LAD (anterior descending branch of the left coronary artery) occlusion and 2 min reperfusion (I/R = 4; NaNO2-I/R = 6), or the heart was removed 24 h later. We have shown that nitrite prevented the I/R-induced increase in cellular and mitochondrial calcium deposits. During simulated I/R, the amplitude of the calcium transient and the diastolic calcium level were significantly lower in the nitrite-treated hearts and the ERP (effective refractory period) fraction of the action potential was significantly increased. Furthermore, nitrite also enhanced the mitochondrial respiratory response and prevented the MPTPT opening during calcium overload. These results suggest that nitrite can reduce the harmful consequences of calcium overload, perhaps directly by modulating ion channels or indirectly by reducing the mitochondrial ROS (reactive oxygen species) production.


Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Cálcio/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Nitrito de Sódio/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Células Cultivadas , Cães , Feminino , Homeostase/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/metabolismo
7.
Biomed Pharmacother ; 118: 109407, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545290

RESUMO

The purpose of this study was to observe the functions of preconditioning with endoplasmic reticulum stress (ERS) whether alleviated heart ischemia/reperfusion injury (HI/RI) via modulating IRE1/ATF6/RACK1/PERK and PGC-1α expressions in diabetes mellitus (DM) or not. Diabetic rats were pretreated with 0.6 mg/kg tunicamycin (TM, 0.6 mg/kg tunicamycin was administered via intraperitoneal injection 30 minutes prior to the I/R procedures), and then subjected to 45 minutes of ischemia and 3 hours of reperfusion. Blood and myocardial tissues were collected, myocardial pathological injuries were investigated, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were measured, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximum rate of left ventricular pressure rise (+dp/dtmax) and maximum rate of left ventricular pressure drop (-dp/dtmax) were evaluated, reactive oxygen species (ROS) and caspase-3 levels were observed, ΔΨm level and ROS expression were measured, and activated transcript factor 6 (ATF6), receptor for activated C kinase 1 (RACK1), PRK-like ER kinase (PERK), glucose regulated protein 78 (GRP78) and peroxisome proliferator-activated receptor γ co-activator 1-α (PGC-1α) expressions were assessed. The TM ameliorated the pathological damages, reduced myocardial oxidative stress damages, restrained apoptosis, and upregulated the expressions of ATF6, RACK1, PERK, GRP78 and PGC-1α compared with those of the ischemia/reperfusion (I/R) group in DM. This study suggested the preconditioning with endoplasmic reticulum stress (TM) strategy that could enhance protection against HI/RI in DM in clinical myocardial diseases.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Diabetes Mellitus Experimental/patologia , Estresse do Retículo Endoplasmático , Proteínas de Membrana/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Quinase C Ativada/metabolismo , eIF-2 Quinase/metabolismo , Animais , Creatina Quinase/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Proteínas de Choque Térmico/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/complicações , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Troponina T/metabolismo
8.
Biomed Pharmacother ; 119: 109418, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505423

RESUMO

YiQiFuMai Powder Injection (YQFM) is widely used in clinical practice for the treatment of heart failure (HF). However, its functional molecular mechanism remains to be fully uncovered. Our present study aimed to elucidate the impact of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced HF. Our results exhibited that YQFM significantly mitigated CAL-induced HF via meliorating the left ventricular contractile function and reducing the serum content of creatine kinase MB (CK-MB), aspartate aminotransferase (AST), interleukin-6 (IL-6), troponin (Tn), myosin, myoglobin (MYO) and myocilin (MYOC). Then, the relevance between circulating omentin level and cardiac function was investigated and we found that serum omentin levels positively associated with ejection fraction and negatively correlated with NT-proBNP content. Further, the effect of YQFM on cardiac function and omentin change in 1, 7 and 14 days CAL-induced HF mice was evaluated and the omentin secretion in isolated subcutaneous (SCAT) and epicardial adipose tissue (EAT) after YQFM treatment were detected. YQFM could increase the circulating omentin content both in 14 days CAL-induced HF mice and isolated EAT. And increased omentin in conditioned medium (CM) could inhibit simulated ischemic/reperfusion (SI/R)-induced cardiomyocytes apoptosis. Moreover, YQFM could ameliorate myocardial apoptosis via positive regulation of AMPK, PI3 K/Akt and negative regulation of MAPKs signaling pathways. Ginsenoside Rd might partially mediated omentin-dependent protective effect of YQFM. Our findings indicated that regulation of cross-talk between adipose tissue and cardiomyocytes might be a potential target through which YQFM exerts cardioprotective effect apart from direct cardiomyocytes protection.


Assuntos
Adipocinas/sangue , Tecido Adiposo/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Injeções , Miócitos Cardíacos/metabolismo , Regulação para Cima , Tecido Adiposo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Doença Crônica , Vasos Coronários/patologia , Creatina Quinase/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Ginsenosídeos/farmacologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ligadura , Masculino , Camundongos Endogâmicos ICR , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Pós , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
9.
Adv Exp Med Biol ; 1127: 117-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140175

RESUMO

Ischemic heart disease is the main cause of morbidity and mortality in the developed world. Although reperfusion therapies are currently the best treatment for this entity, the restoration of blood flow leads, under certain circumstances, to a form of myocardial damage called reperfusion injury. Several studies have shown that age, sex, smoking, diabetes and dyslipidemia are risk factors for cardiovascular diseases. Among these risk factors, dyslipidemias are present in 40% of patients with ischemic heart disease and represent the clinical factor with the greatest impact on the prognosis of patients with cardiovascular diseases. It is known that during reperfusion the increase of the oxidative stress is perhaps one of the most important mechanisms implicated in cell damage. That is why several researchers have studied protective mechanisms against reperfusion injury, such as the ischemic pre- and post- conditioning, making emphasis mainly on the reduction of oxidative stress. However, few of these efforts have been successfully translated into the clinical setting. The controversial results in regards to the relation between cardioprotective mechanisms and dyslipidemia/hypercholesterolemia are mainly due to the difference among quality, composition and the time of administration of hypercholesterolemic diets, as well as the difference in the species used in each of the studies. Therefore, in order to compare results, it is crucial that all variables that could modify the obtained results are taken into consideration.


Assuntos
Dislipidemias/complicações , Isquemia Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/complicações , Estresse Oxidativo , Humanos , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , Fatores de Risco
10.
Oxid Med Cell Longev ; 2019: 2719252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089405

RESUMO

Luteolin has been reported to attenuate ischemia/reperfusion (I/R) injury in the diabetic heart through endothelial nitric oxide synthase- (eNOS-) related antioxidative response. Though the nuclear factor erythroid 2-related factor 2 (Nrf2) is regarded as a key endogenous factor to reduce diabetic oxidative stress, whether luteolin reduces cardiac I/R injury in the diabetic heart via enhancing Nrf2 function needs to be clarified. We hypothesized that pretreatment with luteolin could alleviate cardiac I/R injury in the diabetic heart by affecting the eNOS/Nrf2 signaling pathway. The diabetic rat was produced by a single injection of streptozotocin (65 mg/kg, i.p.) for 6 weeks, and then, luteolin (100 mg/kg/day, i.g.), eNOS inhibitor L-NAME, or Nrf2 inhibitor brusatol was administered for the succedent 2 weeks. After that, the isolated rat heart was exposed to 30 min of global ischemia and 120 min of reperfusion to establish I/R injury. Luteolin markedly ameliorated cardiac function and myocardial viability; upregulated expressions of heme oxygenase-1, superoxide dismutase, glutathione peroxidase, and catalase; and reduced myocardial lactate dehydrogenase release, malondialdehyde, and 8-hydroxydeoxyguanosine in the diabetic I/R heart. All these ameliorating effects of luteolin were significantly reversed by L-NAME or brusatol. Luteolin also markedly reduced S-nitrosylation of Kelch-like ECH-associated protein 1 (Keap1) and upregulated Nrf2 and its transcriptional activity. This effect of luteolin on Keap1/Nrf2 signaling was attenuated by L-NAME. These data reveal that luteolin protects the diabetic heart against I/R injury by enhancing eNOS-mediated S-nitrosylation of Keap1, with subsequent upregulation of Nrf2 and the Nrf2-related antioxidative signaling pathway.


Assuntos
Antioxidantes/metabolismo , Diabetes Mellitus Experimental/complicações , Luteolina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Glicemia/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Hemodinâmica/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , L-Lactato Desidrogenase/metabolismo , Luteolina/farmacologia , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nitrosação , Ratos Sprague-Dawley , Sobrevivência de Tecidos/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
11.
J Transl Med ; 17(1): 127, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992077

RESUMO

BACKGROUND: The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. METHODS: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure-volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. RESULTS: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia-reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. CONCLUSIONS: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.


Assuntos
Canagliflozina/uso terapêutico , Cardiotônicos/uso terapêutico , Endotélio/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Vasodilatação , Aldeídos/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Glicemia/metabolismo , Canagliflozina/farmacologia , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , Glicosúria/complicações , Glicosúria/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sístole/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
12.
Neurol Res ; 41(8): 697-703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31030645

RESUMO

The damage caused by ischemic stroke is mostly refractory to medical therapies and amounts to a substantial degree of mortality and morbidity in the world. The core tenet of treatment for acute ischemic stroke (AIS) is to save 'reversible' ischemic tissue (ischemic penumbra) as quickly as possible within a limited therapeutic time window. The neuroprotective effect of hypothermia has been proven previously in a large number of animal experiments and clinical trials. Some of these animal and human studies have shown that pre-reperfusion hypothermia can reduce myocardial infarction and improve clinical outcomes. However, to date, there is little research about hypothermia before reperfusion in the animal model and human study of AIS. This review will explore possible benefits of the application of pre-reperfusion hypothermia in the setting of AIS.


Assuntos
Isquemia Encefálica/terapia , Hipotermia Induzida/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Acidente Vascular Cerebral/terapia , Animais , Isquemia Encefálica/complicações , Humanos , Traumatismo por Reperfusão Miocárdica/complicações , Acidente Vascular Cerebral/complicações , Resultado do Tratamento
13.
Int J Mol Med ; 43(6): 2451-2461, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017253

RESUMO

Ischemic postconditioning (IPoC) has been demonstrated to prevent myocardial ischemia­reperfusion injury (MIRI), but its cardioprotective effect is abrogated by hypercholesterolemia. The aim of the present study was to determine whether lycopene (LP), a type of carotenoid, can restore the cardioprotective effect of IPoC in hypercholesterolemic rats. Male Wistar rats were fed a cholesterol­enriched diet for 12 weeks to establish a hypercholesterolemic model. The rat hearts were isolated and subjected to 30 min ischemia and 60 min reperfusion using a Langendorff apparatus. LP was administered to the rats intraperitoneally for 5 consecutive days prior to ischemia and reperfusion. Myocardial pathological changes, infarct size and cell apoptosis were measured by hematoxylin and eosin, triphenyltetrazolium chloride and TUNEL staining, respectively. The changes in endoplasmic reticulum (ER) stress markers, the reperfusion injury salvage kinase (RISK) pathway and mitochondrial apoptosis­related proteins were detected by western blotting. Overall, the results demonstrated that low­dose LP in combination with IPoC ameliorated myocardial histopathological changes, reduced the infarct size and release of cardiac enzymes, and decreased cardiomyocyte apoptosis in hypercholesterolemic rats, but no beneficial effects were achieved by the same dose of LP or IPoC treatment were used alone. Furthermore, the combination of LP and IPoC inhibited the expression of glucose­regulated protein 78 and C/EBP homologous protein, increased the phosphorylation levels of AKT, ERK1/2 and glycogen synthase kinase­3ß, repressed mitochondrial permeability transition pore opening, and reduced the expression of cytochrome c, cleaved caspase­9 and cleaved caspase­3. Collectively, these findings demonstrated that LP can restore the cardioprotective effects of IPoC on MIRI in hypercholesterolemic rats, and this restoration by LP was mediated by inhibition of ER stress and reactivation of the RISK pathway in hypercholesterolemic rat myocardium.


Assuntos
Hipercolesterolemia/complicações , Pós-Condicionamento Isquêmico , Licopeno/uso terapêutico , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/terapia , Substâncias Protetoras/uso terapêutico , Animais , Hipercolesterolemia/sangue , Hipercolesterolemia/patologia , Pós-Condicionamento Isquêmico/métodos , Lipídeos/sangue , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos Wistar
14.
Life Sci ; 228: 35-46, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31028804

RESUMO

AIMS: The shortage of donor hearts could be alleviated with the use of the allografts from donation after circulatory death (DCD). Here, we evaluated the protective effect of melatonin on myocardial ischemia/reperfusion (MI/R) injury in a DCD heart model after ex vivo perfusion. MAIN METHODS: Donor hearts were harvested from DCD model rats pre-treated with or without melatonin and subjected to 30 min of ex vivo perfusion, followed by transplantation. Tissue samples were obtained at 3, 12, and 24 h after heart transplantation. Myocardial oedema was evaluated based on the water content and wet/dry ratio, while inflammation was examined with hematoxylin & eosin staining. The expression levels of matrix metalloproteinase-9, interleukin-6, and tumour necrosis factor-α were evaluated. Oxidative stress level was determined from the content of malondialdehyde, activities of superoxide dismutase and glutathione peroxidase, and expression of Nrf2, NQO1 and cytochrome-C. Myocardial apoptosis was detected with TUNEL assay and measurement of the expression levels of Bax, Bcl-2, caspase-3, and cleaved caspase-3. The activation of the JAK2/STAT3 signalling pathway was evaluated by determining the levels of p-JAK2 and p-STAT3. KEY FINDINGS: Melatonin pre-treatment protected the heart from MI/R by reducing myocardial oedema and inflammation, attenuating oxidative stress, and decreasing myocardial apoptosis. Furthermore, the JAK2/STAT3 signalling pathway was activated after melatonin treatment during MI/R. The protective effects of melatonin were abolished by AG490. SIGNIFICANCE: Melatonin pre-treatment protected the heart from MI/R in a DCD heart model after ex vivo perfusion. Melatonin exerted cardioprotective effects through the activation of the JAK2/STAT3 signalling pathway.


Assuntos
Antioxidantes/farmacologia , Transplante de Coração/métodos , Coração/efeitos dos fármacos , Janus Quinase 2/metabolismo , Melatonina/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Animais , Inflamação/complicações , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Preservação de Órgãos/métodos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
15.
Bratisl Lek Listy ; 120(3): 200-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31023038

RESUMO

OBJECTIVES: Aims of this study were to investigate the anti-arrhythmic and cardio-protective effect of atorvastatin and of a new pyridoindole derivative (SMe1EC2) on isolated and perfused hearts while following the Langendorff principles. BACKGROUND: Metabolic syndrome is a widely distributed condition progressing to cardiovascular disease. Many of the metabolic syndrome patients take (HMG)-co-enzyme A (CoA) reductase inhibitors with potential cardio-protective effects. SMe1EC2 is a promising new drug, exerting many positive effects in experimental settings. METHODS: Rats with induced metabolic syndrome were treated with atorvastatin (25 mg/kg) and SMe1EC2 (25 mg/kg and 0.5 mg/kg, respectively) daily for 3 weeks. After the treatment, the hearts were isolated and perfused according to Langendorff. RESULTS: Both atorvastatin and SMe1EC2 improved cardiac function by elevating the left ventricular developed pressure (VLDP) and cardiac contractility. Both SMe1EC2-treated groups improved LVDP during reperfusion, significantly increased ‒dP/dt, and moderately elevated +dP/dt values. The treatment with both atorvastatin and SMe1EC2 (25 mg/kg) significantly reduced malignant arrhythmia in comparison to control group and group treated with SMe1EC2 0.5 mg/kg. CONCLUSIONS: Owing to its anti-arrhythmic and cardio-protective effects, atorvastatin and SMe1EC2 could be of benefit to patients suffering from metabolic syndrome (Tab. 3, Fig. 3, Ref. 41).


Assuntos
Antiarrítmicos , Atorvastatina , Síndrome Metabólica , Traumatismo por Reperfusão Miocárdica , Animais , Antiarrítmicos/farmacologia , Atorvastatina/farmacologia , Coração , Humanos , Síndrome Metabólica/complicações , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ratos , Ratos Wistar
16.
Exp Biol Med (Maywood) ; 244(7): 602-611, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30947537
17.
Int J Cardiol ; 285: 72-79, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904281

RESUMO

AIMS: Remote ischemic conditioning (RIC) is considered a potential clinical approach to reduce myocardial infarct size and ameliorate adverse post-infarct left ventricular (LV) remodeling, however the mechanisms are unknown. The aim was to clarify the impact of RIC on Neuregulin-1 (NRG-1)/ErbBs expression, inflammation and LV hemodynamic function. METHODS AND RESULTS: Male Sprague-Dawley rats were subjected to 30 min occlusion of the left coronary artery (LCA) followed by 2 weeks of reperfusion and separated into three groups: (1) sham operated (without LCA occlusion); (2) Myocardial ischemia/reperfusion (MIR) and (3) remote ischemic perconditioning group (MIR + RIPerc). Cardiac structural and functional changes were evaluated by echocardiography and on the isolated working heart system. The level of H3K4me3 at the NRG-1 promoter, and both plasma and LV tissue levels of NRG-1 were assessed. The expression of pro-inflammatory cytokines, ECM components and ErbB receptors were assessed by RT-qPCR. MIR resulted in a significant decrease in LV function and enlargement of LV chamber. This was accompanied with a decrease in the level of H3K4me3 at the NRG-1 promoter. Consequently NRG-1 protein levels were reduced in the infarcted myocardium. Subsequently, an upregulated influx of CD68+ macrophages, high expression of MMP-2 and -9 as well as an increase of IL-1ß, TLR-4, TNF-α, TNC expression were observed. In contrast, RIPerc significantly decreased inflammation and improved LV function in association with the enhancement of NRG-1 levels and ErbB3 expression. CONCLUSIONS: These findings may reveal a novel anti-remodeling and anti-inflammatory effect of RIPerc, involving activation of NRG-1/ErbB3 signaling.


Assuntos
Ventrículos do Coração/fisiopatologia , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/complicações , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Ecocardiografia , Ventrículos do Coração/diagnóstico por imagem , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos , Ratos Sprague-Dawley
18.
J Pharmacol Sci ; 139(3): 193-200, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827890

RESUMO

Ischemia/reperfusion (I/R)-induced oxidative stress is a serious clinical problem in the reperfusion therapy for ischemic diseases. Tumstatin is an endogenous bioactive peptide cleaved from type IV collagen α3 chain. We previously reported that T3 peptide, an active subfragment of tumstatin, exerts cytoprotective effects on H2O2-induced apoptosis through the inhibition of intracellular reactive oxygen species (ROS) production in H9c2 cardiomyoblasts. In this study, we investigated whether T3 peptide has cardioprotective effects against I/R injury by using in vitro and ex vivo experimental models. H9c2 cardiomyoblasts were stimulated with oxygen and glucose deprivation (OGD) for 12 h followed by reoxygenation for 1-8 h (OGD/R; in vitro model). The cells were treated with T3 peptide (30-1000 ng/ml) during OGD. Ten minutes after the pre-perfusion of T3 peptide (300 ng/ml), Langendorff perfused rat hearts were exposed to ischemia for 30 min followed by reperfusion for 1 h (ex vivo model). T3 peptide inhibited OGD/R-induced apoptosis through the inhibition of mitochondrial ROS production and dysfunction in H9c2 cardiomyoblasts. T3 peptide also prevented I/R-induced cardiac dysfunction, arrhythmia and myocardial infarction in the perfused rat heart. In conclusion, we for the first time demonstrated that T3 peptide exerts cardioprotective effects against I/R injury.


Assuntos
Apoptose/efeitos dos fármacos , Autoantígenos/administração & dosagem , Cardiotônicos/administração & dosagem , Colágeno Tipo IV/administração & dosagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Autoantígenos/química , Autoantígenos/farmacologia , Cardiotônicos/farmacologia , Linhagem Celular , Colágeno Tipo IV/química , Colágeno Tipo IV/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/complicações , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
19.
Circ Heart Fail ; 12(2): e005655, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30764638

RESUMO

BACKGROUND: The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization). METHODS AND RESULTS: The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing-induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization. CONCLUSIONS: The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.


Assuntos
Função do Átrio Direito , Estimulação Cardíaca Artificial , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/etiologia , Traumatismo por Reperfusão Miocárdica/complicações , Função Ventricular Direita , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Frequência Cardíaca , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Marca-Passo Artificial , Proteínas Quinases/metabolismo , Recuperação de Função Fisiológica , Transdução de Sinais , Fatores de Tempo
20.
Eur Heart J Acute Cardiovasc Care ; 8(2): 142-152, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30421619

RESUMO

Reperfusion does not only salvage ischaemic myocardium but can also cause additional cell death which is called lethal reperfusion injury. The time of reperfusion is often accompanied by ventricular arrhythmias, i.e. reperfusion arrhythmias. While both conditions are seen as separate processes, recent research has shown that reperfusion arrhythmias are related to larger infarct size. The pathophysiology of fatal reperfusion injury revolves around intracellular calcium overload and reactive oxidative species inducing apoptosis by opening of the mitochondrial protein transition pore. The pathophysiological basis for reperfusion arrhythmias is the same intracellular calcium overload as that causing fatal reperfusion injury. Therefore both conditions should not be seen as separate entities but as one and the same process resulting in two different visible effects. Reperfusion arrhythmias could therefore be seen as a potential marker for fatal reperfusion injury.


Assuntos
Apoptose , Arritmias Cardíacas/etiologia , Traumatismo por Reperfusão Miocárdica/complicações , Miocárdio/patologia , Animais , Arritmias Cardíacas/patologia , Humanos , Traumatismo por Reperfusão Miocárdica/patologia
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