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1.
An Acad Bras Cienc ; 92(4): e20191148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237136

RESUMO

The current study was designed to investigate the effects and the mechanism of catalpol on myocardial ischemia-reperfusion (MI/R) injury in a diabetic rat model. Male Sprague-Dawley rats were divided into DM + sham, DM +I/R, and DM +I/R + C groups and diabetes was induced using single injections of streptozotocin (STZ; 70 mg/kg; i.p). After confirming the induction of diabetes, rats were administered physiological saline and catalpol (10 mg/kg; i.p.) daily for 28 days. Subsequently, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 30 min followed by reperfusion for 2 h. Haemodynamic parameters were recorded throughout surgery, and following sacrifice, hearts were isolated for biochemical, histopathological, and molecular analyses. Catalpol treatment significantly ameliorated MI/R injury by improving cardiac function, normalizing myocardial enzyme activities and markers of oxidative stress, and by maintaining myocardial architecture. Furthermore, expression levels of the inflammatory cytokines TNF-α and IL-6 were decreased in biochemical and immunohistochemical studies. Additionally, the cardioprotective effects of catalpol were partly related to reductions in myocardial endoplasmic reticulum stress (ERS). In conclusion, catalpol exerts cardioprotective effects in diabetic rats by attenuating inflammation and inhibiting ERS.


Assuntos
Diabetes Mellitus Experimental , Traumatismo por Reperfusão Miocárdica , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse do Retículo Endoplasmático , Glucosídeos Iridoides , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Estreptozocina
2.
Zhongguo Zhong Yao Za Zhi ; 45(17): 4183-4195, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33164403

RESUMO

Acute myocardial infarction(AMI) is still the leading cause of death worldwide. At present, the treatment of AMI is mainly to restore the cardiac blood supply through myocardial reperfusion. With the widespread use of coronary artery bypass grafting and percutaneous coronary intervention(PCI), myocardial reperfusion injury is a major clinical problem. Mitochondrial dysfunction is an important pathological basis for myocardial ischemic injury. Therefore, mitochondria can be used as an important target against myocardial damage. In this article, we would briefly review the physiological functions of mitochondrial dynamics-related proteins as well as their pathological mechanisms and pharmacological interventions in treatment of myocardial ischemia-reperfusion injury.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Intervenção Coronária Percutânea , Humanos , Dinâmica Mitocondrial , Proteínas Mitocondriais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico
3.
Biomolecules ; 10(8)2020 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784904

RESUMO

Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion (IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1 24 h after administration, improving heart function, as detected by a significant recovery of the left ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections, together with a significant reduction in the expression of the extracellular matrix-degrading, matrix metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B, CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a, ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32, MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI).


Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Coração/fisiopatologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Suínos , Receptor 4 Toll-Like/metabolismo
4.
Life Sci ; 259: 118162, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32730836

RESUMO

OBJECTIVE: The inhaled sevoflurane (sevo) is known to protect against myocardial ischemia/reperfusion (I/R) injury (MIRI), in which the functions of microRNAs (miRNAs) have been uncovered. However, the effect of sevo regulating miR-204 on this disease remains unknown. This research aims to explore the roles of sevo and miR-204 in the progression of MIRI. METHODS: The MIRI mice models induced by coronary artery ligation were treated by sevo, miR-204 mimics or silenced coactosin-like protein-1 (Cotl1). The pathology of mice myocardial tissues, apoptosis and ultrastructure of cardiomyocytes were observed. The expression of miR-204, Cotl1, Bax and Bcl-2 was determined. The contents of oxidative stress-related factors and inflammatory factors in mouse myocardial tissues were assessed, and the serum levels of indicators that correlated with myocardial infarction were determined as well. The target relation between miR-204 and Cotl1 was confirmed. RESULTS: MiR-204 was down-regulated, and Cotl1 was up-regulated in myocardial tissues of MIRI mice, and Cotl1 was targeted by miR-204. Sevo, elevated miR-204 and inhibited Cotl1 could promote cardiac function of MIRI mice, and protect myocardial tissue against MIRI by repressing the cardiomyocyte apoptosis, oxidative stress and inflammation reaction in MIRI mice. CONCLUSION: We found that sevo could up-regulate miR-204 to ameliorate MIRI in mice by inhibiting Cotl1 expression, which may provide candidates for the MIRI treatment.


Assuntos
Anestésicos Inalatórios/farmacologia , MicroRNAs/biossíntese , Proteínas dos Microfilamentos/antagonistas & inibidores , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sevoflurano/farmacologia , Animais , Progressão da Doença , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
Expert Opin Pharmacother ; 21(15): 1851-1865, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32659185

RESUMO

INTRODUCTION: Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling. AREAS COVERED: In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI). They review important original investigations and trials in various clinical databases for treatments targeting IRI. EXPERT OPINION: Encouraging results observed in many preclinical studies failed to show similar success in attenuating myocardial IRI in large-scale clinical trials. Identification of critical risk factors for IRI and targeting them individually rather than one size fits all approach should be the major focus of future research. Various newer therapies like tocilizumab, anakinra, colchicine, revacept, and therapies targeting the reperfusion injury salvage kinase pathway, survivor activating factor enhancement, mitochondrial pathways, and angiopoietin-like peptide 4 hold promise for the future.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiotônicos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Cardiotônicos/administração & dosagem , Humanos , Terapia de Alvo Molecular , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/imunologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/imunologia , Inibidores da Agregação de Plaquetas/administração & dosagem
6.
Life Sci ; 257: 118083, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32673665

RESUMO

AIMS: To investigate the preclinical pharmacodynamics and mechanism of JLX001 against myocardial ischemia reperfusion (MI/R) for clinical application. MATERIALS AND METHODS: In vivo, SD rats were given intragastric administration for 5 days, and the MI/R model was established by ligating/releasing the left anterior descending coronary artery. In vitro, the oxygen-glucose deprivation/reperfusion (OGD/R) model was established after the drug was pre-incubated for 24 h in H9C2 cells. The infract size was determined by TTC staining. Left ventricular function of MI/R rats was detected by echocardiography. The level of histopathological score was determined by hematoxylin-eosin (HE) staining. The level of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase (CK), lactic dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were determined by relevant kits. The level of apoptosis was measured by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Hoechst staining. The expression of p-Jak2, p-Stat3, Bax, Bcl-2, TNF-α, IL-1ß protein were determined by western blot. KEY FINDINGS: JLX001 can significantly improve left ventricular function, reduce myocardial infract size, histopathological score, the level of MDA, CK, LDH, TNF-α, IL-1ß and the expression of Bax protein, significantly increase the activity of SOD, Bcl-2 protein expression, p-Jak2 protein expression, p-Stat3 protein expression in rat heart tissues and H9C2 cells. These effects can be reversed by AG490 which is a specific inhibitor of Jak2-Stat3 pathway. SIGNIFICANCE: JLX001 can alleviate MI/R injury by inhibiting myocardial apoptosis, inflammation, and oxidative stress via Jak2-Stat3 pathway in vivo and in vitro.


Assuntos
Janus Quinase 2/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Triterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tirfostinas/farmacologia
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 958-964, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701234

RESUMO

OBJECTIVE: To investigate the protective effect of melatonin against myocardial ischemia reperfusion (IR) injury in isolated rat hearts and explore the underlying mechanisms. METHODS: The isolated hearts from 40 male SD rats were randomly divided into 4 groups (n=10): the control group, where the hearts were perfused with KH solution for 175 min; IR group, where the hearts were subjected to global ischemia for 45 min followed by reperfusion for 120 min; IR+melatonin (Mel+IR) group, where melatonin (5 µmol/L) was administered to the hearts 1 min before ischemia and during the first 5 min of reperfusion, followed by 115 min of reperfusion; and IR+2, 3-butanedione monoxime (IR+BDM) group, where the hearts were treated with BDM (20 mmol/L) in the same manner as melatonin treatment. Myocardial injury in the isolated hearts was assessed based on myocardial injury area, caspase-3 activity, and expressions of cytochrome C and cleaved caspase-3 proteins. Cardiac contracture was assessed using HE staining and by detecting lactate dehydrogenase (LDH) activity and the content of cardiac troponin I (cTnI) in the coronary outflow, measurement of left ventricular end-diastolic pressure (LVEDP) and electron microscopy. The content of ATP in the cardiac tissue was also determined. RESULTS: Compared with those in the control group, the isolated hearts in IR group showed significantly larger myocardial injury area and higher caspase-3 activity and the protein expressions of cytochrome C and cleaved caspase-3 with significantly increased LDH activity and cTnI content in the coronary outflow and elevated LVEDP at the end of reperfusion; HE staining showed obvious fractures of the myocardial fibers and the content of ATP was significantly decreased in the cardiac tissue; electron microscopy revealed the development of contraction bands. In the isolated hearts with IR, treatment with Mel or BDM significantly reduced the myocardial injury area, caspase-3 activity, and protein expressions of cytochrome C and cleaved caspase-3, obviously inhibited LDH activity, lowered the content of cTnI and LVEDP, reduced myocardial fiber fracture, and increased ATP content in the cardiac tissue. Both Mel and BDM inhibited the formation of contraction bands in the isolated hearts with IR injury. CONCLUSIONS: Mel can alleviate myocardial IR injury in isolated rat hearts by inhibiting cardiac contracture, the mechanism of which may involve the upregulation of ATP in the cardiac myocytes to lessen the tear of membrane and reduce cell content leakage.


Assuntos
Coração , Melatonina , Contração Muscular , Traumatismo por Reperfusão Miocárdica , Animais , Coração/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Contração Muscular/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
8.
Life Sci ; 257: 118004, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621918

RESUMO

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.


Assuntos
Dexmedetomidina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Apoptose/efeitos dos fármacos , China , Dexmedetomidina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Isquemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Acta Cir Bras ; 35(3): e202000306, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32692797

RESUMO

PURPOSE: To evaluate whether the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of mitochondrial Ca2+ uniporter (MCU) protects the myocardium against injuries caused by cardiac ischemia and reperfusion (CIR). METHODS: CIR was induced in adult male Wistar rats (300-350 g) by occlusion of the left anterior descendent coronary artery (10 min), followed by reperfusion (120 min). Rats were treated with different doses of MCU blocker ruthenium red (RuR), administered 5 min before ischemia or reperfusion. RESULTS: In untreated rats, the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB) and the lethality (LET) induced by CIR were 85%, 79% and 70%, respectively. In rats treated with RuR before ischemia, the incidences of VA, AVB and LET were significantly reduced to 62%, 25% and 25%, respectively. In rats treated with RuR after ischemia, the incidences of VA, AVB and LET were significantly reduced to 50%, 25% and 25%, respectively. CONCLUSION: The significant reduction of the incidence of CIR-induced VA, AVB and LET produced by the treatment with RuR indicates that the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of MCU can protect the myocardium against injuries caused by CIR.


Assuntos
Canais de Cálcio , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Animais , Cálcio , Canais de Cálcio/efeitos dos fármacos , Masculino , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ratos , Ratos Wistar
10.
Medicine (Baltimore) ; 99(28): e20792, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664071

RESUMO

BACKGROUND: Myocardial ischemia reperfusion injury (MIRI) is 1 of the leading causes of disability and mortality worldwide in the cardiovascular diseases. Acupuncture has been widely applied in the treatment and prevention of cardiovascular diseases in recent years. This systematic review protocol aims to provide the methods for evaluating the efficacy of Neiguan (PC6)-based acupuncture pretreatment in animal models of MIRI. METHODS AND ANALYSIS: The electronic databases of PubMed, Embase, Cochrane Library, as well as the Chinese databases such as China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, China Biology Medicine Database and WanFang Database will be searched from inception to November 2019. The outcome measures were myocardial infarct size, the level of ST-segment elevation, left ventricular ejection fraction, shortening fraction, arrhythmia score, cardiac enzymes, and cardiac troponin. Study inclusion, data extraction and quality assessment will be performed independently by 2 reviewers. RevMan 5.3 software will be used for the data synthesis and the quality of each study will be assessed independently by using the Collaborative Approach To Meta-Analysis And Review Of Animal Data From Experimental Studies checklist with minor modification. RESULTS: This review will provide a high-quality synthesis of Neiguan (PC6)-based acupuncture pretreatment for MIRI in animal models CONCLUSIONS:: This systematic review will provide conclusive evidence for whether Neiguan (PC6)-based acupuncture pretreatment is an effective intervention in animal models of MIRI. TRIAL REGISTRATION NUMBER: PROSPERO CRD42020175144.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Terapia por Acupuntura/métodos , Animais , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , China/epidemiologia , Estudos de Avaliação como Assunto , Modelos Animais , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/mortalidade , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
11.
Medicine (Baltimore) ; 99(26): e20856, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590785

RESUMO

BACKGROUND: At present, there is no effective therapy for preventing myocardial ischemia reperfusion injury (MIRI), and it is inevitable. The methods how to effectively decrease MIRI have attracted the attention of medical researches in recent years. Quercetin is a part of natural flavonoids in plant polyphenols. Many studies have found that quercetin has a positive effect on MIRI. METHODS: In order to clarify the effectiveness and potential mechanisms of quercetin for MIRI animals, we searched for animal studies of quercetin for MIRI in Wanfang data Information, Chinese National Knowledge Infrastructure, VIP information database, China Biology Medicine disc, EMBASE, PubMed, and Web of Science. Participant intervention comparator outcomes of this study are as flowing: P, rats in MIRI; I, received quercetin treatment merely; C, received only vehicle or no treatment; O, Main outcomes are myocardial infarction size and markers of myocardial injury. Additional outcomes are serum indices or protein levels tied to the mechanisms of quercetin in myocardial l/R injury. Review Manager 5.2 software and Stata14.0 will be used for data analysis. SYRCLE's risk of bias tool will be used for risk of bias analysis of animal studies. DISCUSSION: This preclinical systematic review and meta-analysis will evaluate the effects and mechanisms of quercetin for MIRI animals, and provide more evidence-based guidance for transforming basic research into clinical treatment. TRIAL REGISTRATION: INPLASY202050067, registered on 16/5/2020.


Assuntos
Protocolos Clínicos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Quercetina/uso terapêutico , Antioxidantes/uso terapêutico , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
12.
Korean J Radiol ; 21(6): 647-659, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32410404

RESUMO

OBJECTIVE: The occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI). MATERIALS AND METHODS: Fifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement. RESULTS: The extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001). CONCLUSION: APT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.


Assuntos
Apirase/uso terapêutico , Ventrículos do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Apirase/genética , Apirase/metabolismo , Esquema de Medicação , Feminino , Infusões Intravenosas , Modelos Lineares , Microvasos/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Efeito Placebo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
13.
Life Sci ; 256: 117855, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32473245

RESUMO

OBJECTIVE: Subjects with type 2 diabetes (T2D) have lower circulating hydrogen sulfide (H2S) levels following myocardial ischemia and a higher risk of mortality. The aim of this study was to determine the dose-dependent favorable effects of sodium hydrosulfide (NaSH) on myocardial ischemia-reperfusion (IR) injury in rats with T2D. METHODS: T2D was induced using a high-fat diet (HFD) and low-dose of streptozotocin. Rats were divided into control, T2D, and T2D + NaSH groups. NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg) was administered intraperitoneally for 9 weeks. At the end of the study, heart from all rats were isolated and left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) were recorded during baseline and following myocardial IR injury. In addition, infarct size as well as mRNA expression of H2S- and nitric oxide (NO)-producing enzymes were measured. RESULTS: In diabetic rats, NaSH only at doses of 0.56 and 1.6 mg/kg increased recovery of LVDP (16% and 42%), +dp/dt (25% and 35%) and -dp/dt (23% and 32%) as well as decreased infarct size (44% and 35%). At these doses, NaSH increased expressions of cystathionine γ-lyase (CSE) (440% and 271%) and endothelial NO synthase (eNOS) (232% and 148%) but it decreased the expressions of inducible NOS (iNOS) (55% and 71%). NaSH at 0.28, 2.8 and 5.6 mg/kg had no significant effects on these parameters. CONCLUSION: NaSH had a bell-shaped cardioprotective effect against myocardial IR injury in rats with T2D. Higher tolerance to IR injury in heart isolated from type 2 diabetic rats treated with intermediate doses of NaSH is associated with higher CSE-derived H2S and eNOS-derived NO as well as lower iNOS-derived NO.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Cardiotônicos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/complicações , Ratos , Ratos Wistar , Estreptozocina , Sulfetos/administração & dosagem
14.
Mol Cell Biochem ; 468(1-2): 47-58, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162053

RESUMO

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb-lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.


Assuntos
Síndrome Metabólica/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Coração/efeitos dos fármacos , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Nitratos/sangue , Nitritos/sangue
15.
Biochem Biophys Res Commun ; 525(3): 759-766, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145915

RESUMO

Formononetin (FN), a methoxy isoflavone abundant in many plants and herbs, has been evidently proven to possess multiple medicinal properties. Our study aimed to clarify the impact of FN on myocardial ischemia/reperfusion (I/R) injury (MIRI) and the involved mechanism. A rat model of MIRI was produced by ligation and loosening of the left anterior descending (LAD) branch of the coronary artery. Rats received 10 and 30 mg/kg of FN when the reperfusion started. At 24 h after surgery, cardiac function, infarct size, and sera levels of the cardiac markers and inflammatory mediators were measured. To mimic the inflammasome activation in cardiomyocytes, neonatal rat cardiomyocytes (NRCMs) were cultured and treated with lipopolysaccharide (LPS) plus nigericin. Cell death and reactive oxygen species (ROS) were determined. Myocardial expression and activation of the nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome in rats were examined by western blotting. The level of thioredoxin interacting protein (TXNIP)-NLRP3 interaction was assessed. FN notably attenuated cardiac dysfunction, infarct size, release of cardiac markers, and elevation of TNF-α, IL-1ß, and IL-6. FN alleviated LPS plus nigericin-induced injury and ROS increase in NRCMs. Western blotting revealed that FN suppressed the activation of NLRP3 inflammasome and TXNIP-NLRP3 interaction in rats. These findings indicate that FN ameliorated MIRI in rats and inhibited the activation of the NLRP3 inflammasome, at least partially, attributable to suppression of the ROS-TXNIP-NLRP3 pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Isoflavonas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Testes de Função Cardíaca , Inflamassomos/metabolismo , Inflamação/patologia , Isoflavonas/química , Isoflavonas/farmacologia , Lipopolissacarídeos , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Nigericina , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098266

RESUMO

An increased incidence of myocardial infarction (MI) has recently emerged as the cause of cardiovascular morbidity and mortality worldwide. In this study, cardiac function was investigated in a rat myocardial ischemia/reperfusion (I/R) model using echocardiography. Metformin administration significantly increased ejection fraction and fractional shortening values on Days 3 and 7 when MI occurred, indicating that metformin improved left ventricular systolic function. In the Sham + MET and MI + MET groups, the E' value was significantly different up to Day 3 but not at Day 7. This may mean that left ventricular diastolic function was effectively restored to some extent by Day 7 when metformin was administered. These results suggest that diastolic dysfunction, assessed by echocardiography, does not recover in the early phase of ischemic reperfusion injury in the rat myocardial I/R model. However, administering metformin resulted in recovery in the early phase of ischemic reperfusion injury in this model. Further gene expression profiling of left ventricle tissues revealed that the metformin-treated group had notably attenuated immune and inflammatory profiles. To sum up, a rat myocardial I/R injury model and ultrasound-based assessment of left ventricular systolic and diastolic function can be used in translational research and for the development of new heart failure-related drugs, in addition to evaluating the potential of metformin to improve left ventricular (LV) diastolic function.


Assuntos
Ecocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Traumatismo por Reperfusão Miocárdica , Disfunção Ventricular Esquerda , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo
17.
Mol Cell Biochem ; 466(1-2): 129-137, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32056105

RESUMO

This study evaluated the cardioprotective effects of a miR-1275 mimic in a rat model of myocardial ischemia-reperfusion (I/R)-induced myocardial injury (MI). Three groups of rats were established: a sham-operated group, a MI group and a MI+miR-1275 group pretreated for 1 week i.p. with a miR-1275 mimic at a concentration of 30 pmol/mL. MI was induced by I/R. The levels of myocardial enzymes in serum were estimated in all rats, together with haemodynamic functions. The effects of the miR-1275 mimic were determined based on the serum concentrations of inflammatory mediators in the treated vs. sham and MI rats. In addition, western blot assay and immunohistochemical analyses were performed to examine the effect of the miR-1275 mimic on the Wnt/NF-kB signalling pathway in MI rats. Treatment with the miR-1275 mimic attenuated the altered levels of myocardial enzymes and haemodynamic functions seen in MI rats. The myocardial infarct was smaller in rats treated with the miR-1275 mimic than in MI rats. The miR-1275 mimic also reduced myocardiocyte apoptosis and ameliorated the altered Wnt/KF-kB pathway. These results demonstrate the efficacy of the miR-1275 mimic in preventing myocardial I/R-induced MI in rats, by regulating the Wnt/NF-κB pathway.


Assuntos
Apoptose/efeitos dos fármacos , Materiais Biomiméticos/farmacologia , MicroRNAs/farmacologia , Miocárdio/metabolismo , NF-kappa B/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
18.
Mol Immunol ; 120: 61-66, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078859

RESUMO

Myocardial infarction (MI) or heart attack is a deadly event with high prevalence. In the present study, we investigated the effects of the polypeptide copolymer glatiramer acetate (GA) in H9c2 rat cardiomyocytes exposed to oxygen-glucose deprivation/reperfusion injury. Immediately following MI, an acute inflammatory response is triggered that causes activation of various proinflammatory cytokines, infiltration of immune cells, and neovascularization. This response is largely mediated by some genes such as TNF-α, IL-6, ICAM-1, and VEGF. Additionally, the rapid influx of oxidants, such as reactive oxygen species (ROS), leads to a harmful state of oxidative stress. Here, we found that GA could reduce OGD/R-induced inflammation and oxidative stress by inhibiting the expression of TNF-α, IL-6, ICAM-1, and VEGF, and suppressing the production of ROS via reduced NADPH oxidase 1 (NOX1) expression. To elucidate the pathways involved in these promising results, we took a close look at the impact of the endothelial growth response-1 (Egr-1), a transcriptional factor recognized as a mediator of MI-related inflammation and cellular injury. Using siRNA for Egr-1, we found that GA could reduce the expression of ICAM-1 and VEGF by inhibiting Egr-1 expression. Together, our findings indicate a novel therapeutic potential of GA in the treatment of MI.


Assuntos
Cardiotônicos/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Acetato de Glatiramer/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Glucose/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
19.
FASEB J ; 34(2): 3224-3238, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31917470

RESUMO

Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12Rß2 and IL-27Rα receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12Rß2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.


Assuntos
Receptor gp130 de Citocina/metabolismo , Interleucinas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Troponina T/metabolismo
20.
Sci Rep ; 10(1): 23, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913350

RESUMO

Diabetes mellitus (DM) significantly increases myocardial ischemia/reperfusion (MI/R) injury. During DM, cardioprotection induced by conventional pre-conditioning (PreCon) is decreased due to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon with inhaled anesthetic sevoflurane (SF-PreCon) remains cardioprotective during DM, and identified the involved mechanisms. Normal diet (ND) and high-fat diet (HFD)-induced DM mice were randomized into control and SF-PreCon (3 cycles of 15-minute period exposures to 2% sevoflurane) groups before MI/R. SF-PreCon markedly reduced MI/R injury in DM mice, as evidenced by improved cardiac function (increased LVEF and ±Dp/dt), decreased infarct size, and decreased apoptosis. To determine the relevant role of AMPK, the effect of SF-PreCon was determined in cardiac-specific AMPKα2 dominant negative expressing mice (AMPK-DN). SF-PreCon decreased MI/R injury in AMPK-DN mice. To explore the molecular mechanisms responsible for SF-PreCon mediated cardioprotection in DM mice, cell survival molecules were screened. Interestingly, in ND mice, SF-PreCon significantly reduced MI/R-induced activation of p38, a pro-death MAPK, without altering ERK and JNK. In DM and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted. However, SF-PreCon significantly increased phosphorylation of ERK1/2, a pro-survival MAPK in DM and AMPK-DN mice. We demonstrate that SF-PreCon protects the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts cardioprotective action via AMPK-independent activation of a pro-survival MAPK member in DM mice. SF-PreCon may be beneficial compared to conventional PreCon in diabetes or clinical scenarios in which AMPK signaling is impaired.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/complicações , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sevoflurano/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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