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A novel cardioprotective strategy targeting mitochondrial reactive oxygen species production independent of antioxidant activity
Uma nova estratégia cardioprotetora que reduz a produção de ROS mitocondrial independente da atividade antioxidante
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LVEF: left ventricular ejection fraction.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jesús Velásquez-Rodríguez, Vanesa Bruña, Lourdes Vicent, Felipe Díez-Delhoyo, María Jesús Valero-Masa, Iago Sousa-Casasnovas, Miriam Juárez, Carolina Devesa, Francisco Fernández-Avilés, Manuel Martínez-Sellés" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Jesús" "apellidos" => "Velásquez-Rodríguez" ] 1 => array:2 [ "nombre" => "Vanesa" "apellidos" => "Bruña" ] 2 => array:2 [ "nombre" => "Lourdes" "apellidos" => "Vicent" ] 3 => array:2 [ "nombre" => "Felipe" "apellidos" => "Díez-Delhoyo" ] 4 => array:2 [ "nombre" => "María Jesús" "apellidos" => "Valero-Masa" ] 5 => array:2 [ "nombre" => "Iago" "apellidos" => "Sousa-Casasnovas" ] 6 => array:2 [ "nombre" => "Miriam" "apellidos" => "Juárez" ] 7 => array:2 [ "nombre" => "Carolina" "apellidos" => "Devesa" ] 8 => array:2 [ "nombre" => "Francisco" "apellidos" => "Fernández-Avilés" ] 9 => array:2 [ "nombre" => "Manuel" "apellidos" => "Martínez-Sellés" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S087025512100041X?idApp=UINPBA00004E" "url" => "/08702551/0000004000000004/v1_202103300712/S087025512100041X/v1_202103300712/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0870255121000445" "issn" => "08702551" "doi" => "10.1016/j.repc.2020.07.019" "estado" => "S300" "fechaPublicacion" => "2021-04-01" "aid" => "1699" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2021;40:273-81" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Dexmedetomidine attenuates H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>-induced apoptosis of rat cardiomyocytes independently of antioxidant enzyme expression" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "273" "paginaFinal" => "281" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "A dexmedetomidina atenua a apoptose dos cardiomiócitos induzida nos ratos por H2O2 independentemente da expressão das enzima antioxidantes" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1443 "Ancho" => 2175 "Tamanyo" => 146486 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Dexmedetomidine suppresses mRNA expression of superoxide dismutase 2 (SOD2), glutathione peroxidase 4 (GPX4), glutaredoxin 1 (Grx1), and catalase in cardiomyocytes. mRNA expression of antioxidant enzymes was detected by real-time fluorescence quantitative polymerase chain reaction (RT-PCR) analysis. Relative gene expression levels were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Statistical significance was determined using one-way analysis of variance (*p<0.05, **p<0.01, 100 nM vs. control, n=10 per group). 100 nM group: cardiomyocytes treated with dexmedetomidine; H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>: hydrogen peroxide.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Xiaojian Weng, Wenjiao Shi, Xiaodan Zhang, Jianer Du" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Xiaojian" "apellidos" => "Weng" ] 1 => array:2 [ "nombre" => "Wenjiao" "apellidos" => "Shi" ] 2 => array:2 [ "nombre" => "Xiaodan" "apellidos" => "Zhang" ] 3 => array:2 [ "nombre" => "Jianer" "apellidos" => "Du" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255121000445?idApp=UINPBA00004E" "url" => "/08702551/0000004000000004/v1_202103300712/S0870255121000445/v1_202103300712/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "A novel cardioprotective strategy targeting mitochondrial reactive oxygen species production independent of antioxidant activity" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "283" "paginaFinal" => "284" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Henrique Girão, Tania Martins-Marques" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Henrique" "apellidos" => "Girão" "email" => array:1 [ 0 => "hmgirao@fmed.uc.pt" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Tania" "apellidos" => "Martins-Marques" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Clinical Academic Centre of Coimbra (CACC), Coimbra, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Uma nova estratégia cardioprotetora que reduz a produção de ROS mitocondrial independente da atividade antioxidante" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Ischemic heart disease is the leading cause of death worldwide. Chronic or acute occlusion of a coronary artery results in a shortage of oxygen and nutrient supply to some areas of the heart, leading to dramatic myocardial remodeling that includes disturbances of electrical conduction, cardiomyocyte death, inflammation and fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">1,2</span></a> In most cases, the therapeutic strategy involves primary percutaneous coronary intervention (PCI) in order to open up the obstructed coronary artery and restore blood flow. The clinical decision to proceed with PCI is based on the patient's electrocardiographic profile and levels of circulating markers at the time of diagnosis that denote the presence of cardiac lesion. It is therefore of the utmost importance to identify new blood markers that reveal mechanisms of cardiomyocyte injury.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> Cardiac imaging modalities such as positron emission tomography are also important for assessing the myocardial perfusion profile, which reflects the extent of the damage, helping to establish an accurate prognosis as well as the most appropriate therapeutic approach to improve patient outcomes.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although reperfusion by PCI remains the gold standard for treating ischemia-related injury, it is often associated with excessive production of reactive oxygen species (ROS), inducing exacerbated oxidative damage, which results in apoptosis-mediated death of cardiomyocytes, a phenomenon known as ischemia-reperfusion injury. Various strategies have been tried to reduce ischemia-reperfusion injury. Ischemic conditioning, stem cell therapies and aerobic exercise are among the most common non-pharmacological approaches following myocardial infarction. A recent study showed that aerobic exercise training enhances the beneficial effects of stem cell therapy in the left ventricle of rats with moderate infarction, likely inhibiting cardiomyocyte apoptosis.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> Alternatively, pharmacological therapies are often designed to prevent the production of ROS and/or to boost the endogenous antioxidant defenses of cardiomyocytes.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In their study published in the current issue of the <span class="elsevierStyleItalic">Journal</span>, Weng et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> show that dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist, prevents H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>-induced apoptosis of cardiomyocytes by reducing ROS formation. The cardioprotective role of dexmedetomidine has previously been noted: several studies have reported that dexmedetomidine effectively attenuates cell injury and apoptosis, by reducing mitochondrial dysfunction. Surprisingly, in the manuscript by Weng et al.,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> evidence is provided that the cardioprotective effect of dexmedetomidine is not mediated by increased expression of antioxidant enzymes. Thus, it is conceivable that the effect of dexmedetomidine on ROS production is exerted on the mitochondria, the main source of endogenous ROS. For example, reduced mitochondrial membrane potential depolarization was previously observed after dexmedetomidine treatment of H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>-induced oxidative stress injury in cardiomyocytes,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> while dexmedetomidine-mediated activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels contributed to neuroprotection in a cerebral ischemia-reperfusion injury model.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> Mitochondrial ROS are crucial mediators of apoptosis. However, lower levels of ROS are also important to ensure signaling of important cellular processes, such as autophagy and transcriptional activation, and are essential for the protective effects of ischemic conditioning in the heart. In line with this idea, molecules targeting both the activation of mitoKATP channels and ROS generation, such as diazoxide, have been considered viable cardioprotection strategies. Interestingly, the protective effect of diazoxide is lost in connexin43 (Cx43)-deficient cardiomyocytes, which is consistent with an important role of mitochondrial Cx43-dependent production of ROS.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> Although classically associated with gap junction channel-mediated communication and propagation of electrical impulses throughout the heart muscle, localization of Cx43 in mitochondrial membranes has been implicated in the regulation of mitochondrial ion homeostasis, morphology and oxidative metabolism. Importantly, mitochondrial Cx43 levels increase during ischemic preconditioning, likely helping to keep the mitochondrial permeability transition pore in a closed state, delaying the release of apoptotic proteins and preventing cell injury.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> Moreover, the lack of mitochondrial Cx43 prevents the cardioprotective effect of ischemic preconditioning. Nonetheless, the mechanisms and molecular players underlying the trafficking of Cx43 to the mitochondria under physiological and pathological conditions, as well as the exact roles of mitochondrial Cx43, remain unclear.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Excessive oxidative damage caused by ROS-induced ROS release, in which ROS trigger opening of mitochondrial permeability transition pores or anion channels, has been implicated in mitochondrial membrane potential collapse with a consequent increase in ROS generation. Given its putative role as a mitochondrial channel and its association with proteins of the mitochondrial respiratory chain, it is plausible that the effect of dexmedetomidine in reducing ROS production is due to its impact on mitochondrial Cx43. In line with this idea, several studies have shown that dexmedetomidine affects Cx43 homeostasis. For example, it was shown that upregulation of Cx43 mediates the antiarrhythmic effect of dexmedetomidine in ischemic cardiomyopathy, reducing fibrosis and inflammation.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> Another study demonstrated that dexmedetomidine-induced protection against cardiac ischemia-reperfusion injury involves Cx43 and activation of large-conductance Ca2<span class="elsevierStyleSup">+</span>-sensitive potassium channels.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> Moreover, it has been suggested that upregulation of astrocyte Cx43 by dexmedetomidine attenuates brain ischemia-reperfusion injury.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Altogether, the manuscript by Weng et al. is a valuable contribution, demonstrating that dexmedetomidine administration constitutes a potential therapeutic strategy to reduce mitochondrial ROS production in injured cardiomyocytes, which appears to be independent of antioxidant enzyme expression levels. These results may broaden the discussion about alternative protective mechanisms triggered by dexmedetomidine, including via direct impact on the activity of mitochondrial channels.</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">This work was supported by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE) (under the projects PAC ‘NETDIAMOND’ POCI-01-0145-FEDER-016385;</p><p id="par0040" class="elsevierStylePara elsevierViewall">HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323; POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122, FCTUID/NEU/04539/2013, UID/NEU/04539/2019, UIDB/04539/2020, and UIDP/04539/2020).</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EHD1 modulates Cx43 gap junction remodeling associated with cardiac diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 7 | 6 | 13 |
| 2024 Outubro | 64 | 34 | 98 |
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| 2024 Abril | 39 | 31 | 70 |
| 2024 Maro | 32 | 26 | 58 |
| 2024 Fevereiro | 32 | 25 | 57 |
| 2024 Janeiro | 24 | 22 | 46 |
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| 2023 Novembro | 35 | 41 | 76 |
| 2023 Outubro | 28 | 19 | 47 |
| 2023 Setembro | 20 | 23 | 43 |
| 2023 Agosto | 18 | 18 | 36 |
| 2023 Julho | 29 | 12 | 41 |
| 2023 Junho | 33 | 13 | 46 |
| 2023 Maio | 30 | 29 | 59 |
| 2023 Abril | 16 | 15 | 31 |
| 2023 Maro | 32 | 20 | 52 |
| 2023 Fevereiro | 29 | 23 | 52 |
| 2023 Janeiro | 13 | 12 | 25 |
| 2022 Dezembro | 29 | 26 | 55 |
| 2022 Novembro | 47 | 33 | 80 |
| 2022 Outubro | 40 | 26 | 66 |
| 2022 Setembro | 21 | 43 | 64 |
| 2022 Agosto | 27 | 37 | 64 |
| 2022 Julho | 39 | 44 | 83 |
| 2022 Junho | 64 | 32 | 96 |
| 2022 Maio | 68 | 32 | 100 |
| 2022 Abril | 31 | 37 | 68 |
| 2022 Maro | 51 | 44 | 95 |
| 2022 Fevereiro | 24 | 41 | 65 |
| 2022 Janeiro | 19 | 32 | 51 |
| 2021 Dezembro | 24 | 37 | 61 |
| 2021 Novembro | 30 | 37 | 67 |
| 2021 Outubro | 36 | 55 | 91 |
| 2021 Setembro | 15 | 37 | 52 |
| 2021 Agosto | 27 | 42 | 69 |
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