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1.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206441

RESUMO

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.


Assuntos
Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica , Miocárdio , Proteína Desglicase DJ-1/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia
2.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203800

RESUMO

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor ß/δ (PPARß/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARß/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARß/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARß/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARß/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARß/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARß/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARß/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiotônicos/uso terapêutico , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , PPAR delta/metabolismo , PPAR beta/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Antioxidantes/metabolismo , Caderinas/metabolismo , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Catalase/metabolismo , Metabolismo Energético/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR delta/agonistas , PPAR beta/agonistas , Ratos Wistar , Superóxido Dismutase/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Proteína Desacopladora 3/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Life Sci ; 280: 119742, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166712

RESUMO

AIMS: Myocardial ischemia-reperfusion (I/R) injury is considered as a major obstacle of myocardial perfusion to save acute myocardial infarction, and causes a serious threat to human health. An extensive body of evidence has unveiled that mesenchymal stem cells (MSCs) as adult stem cells play a vital role in the field of damaged myocardial regeneration and repair. However, the biological role of MSCs derived-exosomes in the protection of myocardial I/R injury has not been elucidated. MAIN METHODS: In this study, we isolated and characterized MSCs from the bone marrow of rats femur and tibia. H9c2 cells were administrated to established the cellular hypoxia-reoxygenation (H/R) model, and co-cultured with MSCs and MSCs-derived exosomes. KEY FINDINGS: Functional experiments revealed that MSCs and MSCs-derived exosomes inhibited H/R-induced cell apoptosis and cell autophagy. Interestingly, rapamycin as an activator of autophagy reversed the positive effects of MSCs-derived exosomes, while 3-methyladenine (3-MA) as autophagy inhibitor further promoted the effects of MSCs-derived exosomes, indicating MSCs exerted its function on H/R injury by mediating autophagy. Subsequently, we found that CHK2-Beclin2 pathway participated in H/R-induced autophagy. Mechanistically, miR-143-3p directly targeted CHK2 and negatively regulated CHK2 expression. Moreover, repression of exosomal miR-143-3p promoted H/R-induced autophagy via CHK2-Beclin2 pathway. Consistent with the results of in vitro experiments, in vivo experiments confirmed that exosomal miR-143-3p effectively reduced cell apoptosis by regulating autophagy via CHK2-Beclin2 pathway. SIGNIFICANCE: Collectively, our results indicated that MSCs-derived exosomal miR-143-3p might represent a promising option for the treatment of I/R injury.


Assuntos
Autofagia , Exossomos/genética , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Animais , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Regulação para Baixo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos Sprague-Dawley , Regulação para Cima
4.
Cell Prolif ; 54(7): e13051, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33973685

RESUMO

BACKGROUND: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. METHODS AND RESULTS: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. CONCLUSIONS: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.


Assuntos
Autofagia , Precondicionamento Isquêmico , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Animais , Apoptose , Proteína Beclina-1/antagonistas & inibidores , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sirtuína 3/deficiência , Sirtuína 3/genética
5.
Oxid Med Cell Longev ; 2021: 5529810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854692

RESUMO

Impaired function of the endoplasmic reticulum (ER) is followed by evolutionarily conserved cell stress responses, which are employed by cells, including cardiomyocytes, to maintain and/or restore ER homeostasis. ER stress activates the unfolded protein response (UPR) to degrade and remove abnormal proteins from the ER lumen. Although the UPR is an intracellular defense mechanism to sustain cardiomyocyte viability and heart function, excessive activation initiates ER-dependent cardiomyocyte apoptosis. Myocardial ischemia/reperfusion (I/R) injury is a pathological process occurring during or after revascularization of ischemic myocardium. Several molecular mechanisms contribute to the pathogenesis of cardiac I/R injury. Due to the dual protective/degradative effects of ER stress on cardiomyocyte viability and function, it is of interest to understand the basic concepts, regulatory signals, and molecular processes involved in ER stress following myocardial I/R injury. In this review, therefore, we present recent findings related to the novel components of ER stress activation. The complex effects of ER stress and whether they mitigate or exacerbate myocardial I/R injury are summarized to serve as the basis for research into potential therapies for cardioprotection through control of ER homeostasis.


Assuntos
Estresse do Retículo Endoplasmático , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Humanos , Resposta a Proteínas não Dobradas
6.
Biomed Res Int ; 2021: 6661526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791371

RESUMO

Background: Animal models are well established for studying the effects of alkaloids in preventing myocardial ischemia-reperfusion injury. However, few studies have investigated the therapeutic effects of alkaloids in humans. This meta-analysis and systematic review assessed the efficacy of alkaloids in attenuating infarct size in rats with myocardial ischemia-reperfusion injury. Methods: An integrated literature search including the PubMed, Embase, and Cochrane Library databases was performed to identify studies that evaluated the therapeutic effects of alkaloids on myocardial ischemia-reperfusion injury in rats. The main outcome was infarct size, and SYRCLE's risk of bias tool was used to assess the quality of the studies. Results: 22 studies were brought into the meta-analysis. Compared with the effects of vehicle, alkaloids significantly reduced infarct size (standardized mean difference (SMD) = -0.45; 95% confidence interval (CI) = -0.64 to - 0.26). In subgroup analyses, isoquinoline alkaloids (SMD = -0.43; 95%CI = -0.70 to - 0.16) significantly reduced infarct size versus the control. Conclusion: Isoquinoline alkaloids can potentially alleviate myocardial ischemia-reperfusion injury. This meta-analysis and systematic review supply a reference for research programs aiming to develop alkaloid-based clinical drugs. This trial is registered with CRD42019135489.


Assuntos
Alcaloides/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos
7.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922385

RESUMO

Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil's activation, such as Interleukin 1 beta (IL-1ß) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.


Assuntos
Suplementos Nutricionais , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfatidilserinas/farmacologia , Disfunção Ventricular Esquerda/complicações , Remodelação Ventricular/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/fisiologia
8.
Nutr Metab Cardiovasc Dis ; 31(6): 1916-1928, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895078

RESUMO

BACKGROUND AND AIMS: Myocardial ischemia/reperfusion injury (MI/RI) is a result of coronary revascularization, and often increases cell apoptosis and autophagy. Downregulated cellular FADD-like-IL-1ß-converting enzyme-inhibitory protein (cFLIP) was associated with development of several myocardial diseases, whether overexpression of cFLIP can attenuate MI/RI remains unclear. This study aimed to determine the effects of cFLIP on apoptosis and autophagy in MI/RI. METHODS AND RESULTS: Ischemia/reperfusion (I/R) rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. Both I/R injury and H/R injury down-regulated expression of two cFLIP isoforms (cFLIPL and cFLIPS), and instigated apoptosis and autophagy simultaneously. Overexpression of cFLIPL and/or cFLIPS led to a significant increase in cardiomyocytes viability in vitro, and also reduced the myocardial infarct volume in vivo, these changes were associated with suppressed apoptosis and autophagy. Mechanistically, overexpression of cFLIP significantly downregulated pro-apoptotic molecules (Caspase-3, -8, -9), and pro-autophagic molecules (Beclin-1 and LC3-II). Moreover, cFLIP significantly suppressed activity of NF-κB pathway to upregulate the expression of Bcl-2, which is the molecular of interplay of apoptosis and autophagy. CONCLUSION: Overexpression of cFLIP significantly attenuated MI/RI both in vivo and vitro via suppression of apoptosis and lethal autophagy. cFLIP can suppress activity of NF-κB pathway, and further upregulated expression of Bcl-2.


Assuntos
Apoptose , Autofagia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Células Cultivadas , Modelos Animais de Doenças , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima
9.
Aging (Albany NY) ; 13(8): 11135-11149, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819187

RESUMO

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.


Assuntos
Fator 4 Ativador da Transcrição/genética , Proteínas de Ciclo Celular/metabolismo , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/genética , Fatores de Processamento de RNA/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Butilaminas/farmacologia , Butilaminas/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Metilação , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores de Processamento de RNA/antagonistas & inibidores , Fatores de Processamento de RNA/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
10.
Life Sci ; 274: 119327, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33711390

RESUMO

This study aimed to explore the potential target of the cardio-protective effect induced by sevoflurane anesthesia based on evidence from clinical samples and in vitro model. Forty patients undergoing mitral valve replacement were randomly allocated to receive sevoflurane or propofol-based anesthesia. Atrial muscle specimens were collected from all patients, of which 5 were used to perform transcriptomics analysis. The cTn-I concentration was tested before, at the end of, and 24 h after surgery. In in vitro study, the expression level of the identified target gene, i.e., THAP11, was studied in H9C2 cells treated with sevoflurane or propofol. Then, we studied cell viability using CCK-8 staining, apoptosis by using flow cytometry, and cell death by lactic acid dehydrogenase (LDH) detection in H9C2 cells exposed to oxygen glucose deprivation/reoxygenation (OGD/R) injury. THAP11 was the most significantly down-regulated gene in the transcriptomics analysis (P < 0.001), as confirmed in validation samples (P = 0.006). THAP11 mRNA levels in atrial muscle specimens were positively associated with cTn-I levels at 24-h postoperatively (determination coefficient = 0.564; P < 0.001). Sevoflurane treatment down-regulated THAP11 in H9C2 cell models, which promoted cell viability, inhibited cell apoptosis, and death in the OGD/R injury cell model. Up-regulation of THAP11 reduced the protective effect of sevoflurane treatment against OGD/R injury. Sevoflurane anesthesia down-regulates the expression of THAP11, which contributes to a cardio-protective effect. THAP11 down-regulation promotes cell viability, and inhibits cell apoptosis and death, thereby protecting again myocardial injury; it may therefore be a novel target for perioperative cardio-protection.


Assuntos
Cardiotônicos/farmacologia , Insuficiência da Valva Mitral/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Repressoras/antagonistas & inibidores , Sevoflurano/farmacologia , Anestésicos Inalatórios/farmacologia , Animais , Apoptose , Sobrevivência Celular , Regulação para Baixo , Feminino , Glucose/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/metabolismo , Insuficiência da Valva Mitral/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxigênio/metabolismo , Ratos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
11.
Eur J Pharmacol ; 898: 173999, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33675785

RESUMO

Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.


Assuntos
Desferroxamina/farmacologia , Ferroptose/efeitos dos fármacos , Imidazóis/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Piridazinas/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais
12.
Mol Biol Rep ; 48(3): 2507-2518, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33755849

RESUMO

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia-reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.


Assuntos
Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Necroptose , Nucleobindinas/uso terapêutico , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Eletrocardiografia , Fibrose , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Necroptose/efeitos dos fármacos , Nucleobindinas/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
13.
Am J Physiol Heart Circ Physiol ; 320(5): H1813-H1821, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33666503

RESUMO

Although peroxisomes have been extensively studied in other cell types, their presence and function have gone virtually unexamined in cardiac myocytes. Here, in neonatal rat ventricular myocytes (NRVM) we showed that several known peroxisomal proteins co-localize to punctate structures with a morphology typical of peroxisomes. Surprisingly, we found that the peroxisomal protein, fatty acyl-CoA reductase 1 (FAR1), was upregulated by pharmacological and pathophysiological ER stress induced by tunicamycin (TM) and simulated ischemia-reperfusion (sI/R), respectively. Moreover, FAR1 induction in NRVM was mediated by the ER stress sensor, activating transcription factor 6 (ATF6). Functionally, FAR1 knockdown reduced myocyte death during oxidative stress induced by either sI/R or hydrogen peroxide (H2O2). Thus, Far1 is an ER stress-inducible gene, which encodes a protein that localizes to peroxisomes of cardiac myocytes, where it reduces myocyte viability during oxidative stress. Since FAR1 is critical for plasmalogen synthesis, these results imply that plasmalogens may exert maladaptive effects on the viability of myocytes exposed to oxidative stress.NEW & NOTEWORTHY The peroxisomal enzyme, FAR1, was shown to be an ER stress- and ATF6-inducible protein that localizes to peroxisomes in cardiac myocytes. FAR1 decreases myocyte viability during oxidative stress.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Aldeído Oxirredutases/biossíntese , Estresse do Retículo Endoplasmático , Traumatismo por Reperfusão Miocárdica/enzimologia , Miócitos Cardíacos/enzimologia , Peroxissomos/enzimologia , Fator 6 Ativador da Transcrição/genética , Aldeído Oxirredutases/genética , Animais , Animais Recém-Nascidos , Hipóxia Celular , Sobrevivência Celular , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Indução Enzimática , Peróxido de Hidrogênio/toxicidade , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Ratos , Tunicamicina/toxicidade
14.
Biomed Res Int ; 2021: 8870674, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763489

RESUMO

Objective: This study is aimed at investigating the therapeutic effects of tetrandrine (Tet) on myocardial ischemia reperfusion (I/R) injury and probe into underlying molecular mechanism. Methods: H9C2 cells were divided into hypoxia/oxygenation (H/R) group, H/R+Tet group, H/R+Tet+negative control (NC) group, and H/R+Tet+miR-202-5p inhibitor group. RT-qPCR was utilized to monitor miR-202-5p and TRPV2 expression, and TRPV2 protein expression was detected via western blot and immunohistochemistry in H9C2 cells. Cardiomyocyte apoptosis was evaluated through detection of apoptosis-related markers and flow cytometry. Furthermore, myocardial enzyme levels were detected by ELISA. Rats were randomly separated into sham operation group, I/R group, I/R+Tet group (50 mg/kg), I/R+Tet+NC group, and I/R+Tet+miR-202-5p inhibitor group. miR-202-5p and TRPV2 mRNA expression was assessed by RT-qPCR. TRPV2 protein expression was detected through western blot and immunohistochemistry in myocardial tissues. Apoptotic levels were assessed via apoptosis-related proteins and TUNEL. Pathological changes were observed by H&E staining. Myocardial infarction size was examined by Evans blue-TCC staining. Results: Abnormally expressed miR-202-5p as well as TRPV2 was found in H/R H9C2 cells and myocardial tissues of I/R rats, which was ameliorated following Tet treatment. Tet treatment significantly suppressed H/R- or I/R-induced cardiomyocyte apoptosis. ELISA results showed that CK-MB and LDH levels were lowered by Tet treatment in H/R H9C2 cells and serum of I/R rats. H&E staining indicated that Tet reduced myocardial injury in I/R rats. Also, myocardial infarction size was lowered by Tet treatment. The treatment effects of Tet were altered following cotreatment with miR-202-5p inhibitor. Conclusion: Our findings revealed that Tet may ameliorate myocardial I/R damage via targeting the miR-202-5p/TRPV2 axis.


Assuntos
Benzilisoquinolinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/biossíntese , Traumatismo por Reperfusão Miocárdica , Miocárdio , Miócitos Cardíacos , Canais de Cátion TRPV/biossíntese , Animais , Linhagem Celular , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley
15.
Int J Mol Sci ; 22(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673646

RESUMO

Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a hyperosmolar solution-is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties-e.g., perioperative neuroprotection-are described. However, whether Mannitol also confers cardioprotection via a pre- and/or postconditioning stimulus, possibly reducing consequences of I/R injury, remains to be seen. Therefore, in the present study we investigated whether (1) Mannitol-induced pre- and/or postconditioning induces myocardial infarct size reduction and (2) activation of mitochondrial ATP-sensitive potassium (mKATP) channels is involved in cardioprotection by Mannitol. Experiments were performed on isolated hearts of male Wistar rats via a pressure controlled Langendorff system, randomized into 7 groups. Each heart underwent 33 min of global ischemia and 60 min of reperfusion. Control hearts (Con) received Krebs-Henseleit buffer as vehicle only. Pre- and postconditioning was achieved by administration of 11 mmol/L Mannitol for 10 min before ischemia (Man-PC) or immediately at the onset of reperfusion (Man-PoC), respectively. In further groups, the mKATP channel blocker 5HD, was applied with and without Mannitol, to determine the potential underlying cardioprotective mechanisms. Primary endpoint was infarct size, determined by triphenyltetrazolium chloride staining. Mannitol significantly reduced infarct size both as a pre- (Man-PC) and postconditioning (Man-PoC) stimulus compared to control hearts (Man-PC: 31 ± 4%; Man-PoC: 35 ± 6%, each p < 0.05 vs. Con: 57 ± 9%). The mKATP channel inhibitor completely abrogated the cardioprotective effect of Mannitol-induced pre- (5HD-PC-Man-PC: 59 ± 8%, p < 0.05 vs. Man-PC) and postconditioning (5HD-PoC-Man-PoC: 59 ± 10% vs. p < 0.05 Man-PoC). Infarct size was not influenced by 5HD itself (5HD-PC: 60 ± 14%; 5HD-PoC: 54 ± 14%, each ns vs. Con). This study demonstrates that Mannitol (1) induces myocardial pre- and postconditioning and (2) confers cardioprotection via activation of mKATP channels.


Assuntos
Cardiotônicos/farmacologia , Precondicionamento Isquêmico Miocárdico/métodos , Manitol/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Canais de Potássio/metabolismo , Animais , Diuréticos Osmóticos/farmacologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Distribuição Aleatória , Ratos , Ratos Wistar
16.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760122

RESUMO

Myocardial ischemia­reperfusion injury (MIRI) is a severe injury to the ischemic myocardium following the recovery of blood flow. Currently, there is no effective treatment for MIRI in clinical practice. Over the past two decades, biological studies of hypoxia and hypoxia­inducible factor­1α (HIF­1α) have notably improved understanding of oxygen homeostasis. HIF­1α is an oxygen­sensitive transcription factor that mediates adaptive metabolic responses to hypoxia and serves a pivotal role in MIRI. In particular, previous studies have demonstrated that HIF­1α improves mitochondrial function, decreases cellular oxidative stress, activates cardioprotective signaling pathways and downstream protective genes and interacts with non­coding RNAs. The present review summarizes the roles and associated mechanisms of action of HIF­1α in MIRI. In addition, HIF­1α­associated MIRI intervention, including natural compounds, exosomes, ischemic preconditioning and ischemic post­processing are presented. The present review provides evidence for the roles of HIF­1α activation in MIRI and supports its use as a therapeutic target.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão/genética , Apoptose/genética , Humanos , Precondicionamento Isquêmico , Mitocôndrias/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/genética
17.
Mol Cell Biochem ; 476(7): 2675-2684, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33666828

RESUMO

Inhibition of succinate dehydrogenase (SDH) by Dimethyl Malonate (DiMal) reduces cardiac ischemia-reperfusion (IR) injury. We investigated the cardioprotective effect of DiMal in a rat model during advancing type 2 diabetes. Zucker Diabetic Fatty rats and lean controls were investigated corresponding to prediabetes, onset and mature diabetes. Hearts were mounted in an isolated perfused model, and subjected to IR for investigation of infarct size (IS) and mitochondrial respiratory control ratio (RCR). DiMal was administered for 10 min before ischemia. Compared with age-matched non-diabetic rats, prediabetic rats had larger IS (49 ± 4% vs. 36 ± 2%, p = 0.007), rats with onset diabetes smaller IS (51 ± 3% vs. 62 ± 3%, p = 0.05) and rats with mature diabetes had larger IS (79 ± 3% vs. 69 ± 2%, p = 0.06). At the prediabetic stage DiMal did not alter IS. At onset of diabetes DiMal 0.6 mM increased IS in diabetic but not in non-diabetic control rats (72 ± 4% vs. 51 ± 3%, p = 0.003). At mature diabetes DiMal 0.1 and 0.6 mM reduced IS (68 ± 3% vs. 79 ± 3% and 64 ± 5% vs. 79 ± 3%, p = 0.1 and p = 0.01), respectively. DiMal 0.1 mM alone reduced IS in age-matched non-diabetic animals (55 ± 3% vs. 69 ± 2% p = 0.01). RCR was reduced at mature diabetes but not modulated by DiMal. Modulation of SDH activity results in variable infarct size reduction depending on presence and the stage of diabetes. Modulation of SDH activity may be an unpredictable cardioprotective approach.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Traumatismo por Reperfusão Miocárdica , Miocárdio , Succinato Desidrogenase , Animais , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/enzimologia , Miocárdio/patologia , Ratos , Ratos Zucker , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo
18.
Mol Cell Biochem ; 476(7): 2803-2812, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33725228

RESUMO

We aimed to investigate the protective role and mechanism of dexmedetomidine (DEX) on H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R) injury. Six experimental groups were designed as follows: normal control group (group C), H/R group, H/R + DEX group, H/R + gastrodin group, H/R + Ex527 (SIRT1 inhibitor) group, and H/R + DEX + Ex527 group. Lactate dehydrogenase (LDH) activity and the levels of oxidative stress-related enzymes such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were measured using corresponding commercial kits. Cell counting kit (CCK)-8 assay was used to detect cell survival rate while flow cytometry and caspase 3/7 activity were used to determine cell apoptosis, respectively. Western blot was used to detect the expression of silent information regulator 1 (SIRT1), C/EBP homologous protein (CHOP), cleaved-caspase-12/3 and pro-caspase-12/3 in each group. From our findings, when compared with H/R, H/R + Ex527 and H/R + DEX + Ex527 groups, DEX pretreatment of cells in H/R + DEX group significantly increased cell survival rate, and simultaneously reduced LDH activity, oxidative stress and the apoptosis rate of H9c2 cells with H/R injury. Moreover, DEX up-regulated SIRT1 expression level and down-regulated the levels of endoplasmic reticulum (ER) stress-related markers such as CHOP, cleaved-caspase-12 and cleaved-caspase-3, respectively. Ex527 could completely block DEX-induced upregulated expression of SIRT1, and partially blocked the DEX-induced downregulated expression levels of CHOP, cleaved-caspase-12 and cleaved-caspase-3. These results proved that DEX reversed H/R injury-induced oxidative stress and ER stress-dependent apoptosis of cardiomyocytes via SIRT1/CHOP signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Dexmedetomidina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Fator de Transcrição CHOP/metabolismo , Animais , Linhagem Celular , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Ratos
19.
Acta Biochim Biophys Sin (Shanghai) ; 53(4): 430-437, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33686403

RESUMO

Resveratrol (RES) protects myocardial cells from hypoxia/reoxygenation (H/R)-caused injury. However, the mechanism of this effect has not been clarified. Thus, in this study, we aimed to determine whether RES attenuates H/R-induced cell necroptosis by inhibiting the tumor necrosis factor-alpha (TNF-α)/receptor-interacting protein kinase 1 (RIP1)/RIP3/mixed-lineage kinase domain-like (MLKL) signaling pathway. Rat myocardial ischemia/reperfusion (I/R) models and H/R-injured cell models were constructed. Our study showed that myocardial H/R injury significantly increased the levels of TNF-α, RIP1, RIP3, and p-MLKL/MLKL by western blot analysis. Cell viability assay and 4,6-dianmidino-2-phenylindole (DAPI)-propidium iodide staining showed that the cell viability was decreased, and necroptosis was increased after myocardial H/R injury. The expressions of TNF-α, RIP1, RIP3, and p-MLKL/MLKL in H/R myocardial cells treated with different concentrations of RES were significantly downregulated. In addition, we also found that the cell viability was increased and necroptosis was decreased in dose-dependent manners when H/R-injured cells were treated with RES. In addition, the enhanced effect of TNF-α on necroptosis in myocardial H/R-injured cells was improved by RES, and the effect of RES was confirmed in vivo in I/R rats. This study also showed that RES suppresses necroptosis in H9c2 cells, which may occur through the inhibition of the TNF-α/RIP1/RIP3/MLKL signaling pathway. Our data suggest that necroptosis is a promising therapeutic target and may be a promising therapeutic target for the treatment of myocardial I/R injury.


Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , Necroptose/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley
20.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567578

RESUMO

Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) into numerous lipid mediators, oxylipids, which are further metabolised by soluble epoxide hydrolase (sEH), reducing their activity. The objective of this study was to characterize oxylipid metabolism in the left ventricle (LV) following ischemic injury in females. Human LV specimens were procured from female patients with ischemic cardiomyopathy (ICM) or non-failing controls (NFC). Female C57BL6 (WT) and sEH null mice averaging 13-16 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD) to induce myocardial infarction. WT (wild type) mice received vehicle or sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB), in their drinking water ad libitum for 28 days. Cardiac function was assessed using echocardiography and electrocardiogram. Protein expression was determined using immunoblotting, mitochondrial activity by spectrophotometry, and cardiac fibre respiration was measured using a Clark-type electrode. A full metabolite profile was determined by LC-MS/MS. sEH was significantly elevated in ischemic LV specimens from patients, associated with fundamental changes in oxylipid metabolite formation and significant decreases in mitochondrial enzymatic function. In mice, pre-treatment with tAUCB or genetic deletion of sEH significantly improved survival, preserved cardiac function, and maintained mitochondrial quality following MI in female mice. These data indicate that sEH may be a relevant pharmacologic target for women with MI. Although future studies are needed to determine the mechanisms, in this pilot study we suggest targeting sEH may be an effective strategy for reducing ischemic injury and mortality in middle-aged females.


Assuntos
Envelhecimento , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/fisiologia , Coração/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Estudos de Casos e Controles , Família 2 do Citocromo P450/fisiologia , Epóxido Hidrolases/antagonistas & inibidores , Feminino , Coração/fisiopatologia , Humanos , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Taxa de Sobrevida , Espectrometria de Massas em Tandem
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