RESUMO

The use of cardioprotective strategies as adjuvants of cardioplegic solutions has become an ideal alternative for the improvement of post-surgery heart recovery. The choice of the optimal cardioplegia, as well as its distribution mechanism, remains controversial in the field of cardiovascular surgery. There is still a need to search for new and better cardioprotective methods during cardioplegic procedures. New techniques for the management of cardiovascular complications during cardioplegia have evolved with new alternatives and additives, and each new strategy provides a tool to neutralize the damage after ischemia/reperfusion events. Researchers and clinicians have committed themselves to studying the effect of new strategies and adjuvant components with the potential to improve the cardioprotective effect of cardioplegic solutions in preventing myocardial ischemia/reperfusion-induced injury during cardiac surgery. The aim of this review is to explore the different types of cardioplegia, their protection mechanisms, and which strategies have been proposed to enhance the function of these solutions in hearts exposed to cardiovascular pathologies that require surgical alternatives for their corrective progression.

RESUMO

Small extracellular vesicles are nanosized vesicles (30-200 nm) that can ferry proteins, nucleic acids, and lipids between cells and therefore, have significant potential as biomarkers, drug delivery tools or therapeutic agents. SEVs of endothelial origin have been shown to -among other functions-reduce in vitro ischemia/reperfusion (I/R) injury in cardiomyocytes, but whether a pro-inflammatory state of the endothelium impairs the functionality of these SEVs remains to be elucidated. To test this, human umbilical vein endothelial cells cells were treated with TNF-α 10 ng/mL and the expression of the pro-inflammatory parameters VCAM-1, ICAM-1 and eNOS were determined by Western blot. SEVs were isolated from endothelial cells treated with or without TNF-α 10 ng/mL using size exclusion chromatography. The size and concentration of SEVs was measured by Nanoparticle Tracking Analysis. The expression of the surface marker CD81 was determined by immunoassay, whereas their morphology was assessed by electron microscopy. The function of endothelial SEVs was assessed by evaluating their cardioprotective effect in an ex vivo model of global I/R using isolated hearts from adult C57BL/6 mice. Treatment of HUVECs with TNF-α induced the expression of VCAM-1 and ICAM-1, whereas eNOS levels were decreased. TNF-α did not affect the production, size, morphology, or expression of CD81. SEVs significantly reduced the infarct size as compared with untreated mice hearts, but SEVs isolated from TNF-α treated cells were unable to achieve this effect. Therefore, a pro-inflammatory state induced by TNF-α does not alter the production of endothelial SEVs but impairs their function in the setting of I/R injury.

RESUMO

INTRODUCTION: The vascular cell adhesion molecule (VCAM-1) is a transmembrane sialoglycoprotein detected in activated endothelial and vascular smooth muscle cells involved in the adhesion and transmigration of inflammatory cells into damaged tissue. Widely used as a pro-inflammatory marker, its potential role as a targeting molecule has not been thoroughly explored. AREAS COVERED: We discuss the current evidence supporting the potential targeting of VCAM-1 in atherosclerosis, diabetes, hypertension and ischemia/reperfusion injury. EXPERT OPINION: There is emerging evidence that VCAM-1 is more than a biomarker and may be a promising therapeutic target for vascular diseases. While there are neutralizing antibodies that allow preclinical research, the development of pharmacological tools to activate or inhibit this protein are required to thoroughly assess its therapeutic potential.

Assuntos

Aterosclerose , Traumatismo por Reperfusão , Humanos , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/uso terapêutico , Aterosclerose/tratamento farmacológico , Endotélio Vascular

RESUMO

Introduction: Short episodes of ischemia-reperfusion (IR) in the heart (classical ischemic preconditioning, IPC) or in a limb (remote ischemic preconditioning, RIPC) before a prolonged ischemic episode, reduce the size of the infarct. It is unknown whether IPC and RIPC share common mechanisms of protection. Animals KO for NOX2, a superoxide-producing enzyme, or KO for NLRP3, a protein component of inflammasome, are not protected by IPC. The aim of this study was to investigate if NOX2 or NLRP3 inflammasome are involved in the protection induced by RIPC. Methods: We preconditioned rats using 4 × 5 min periods of IR in the limb with or without a NOX2 inhibitor (apocynin) or an NLRP3 inhibitor (Bay117082). In isolated hearts, we measured the infarct size after 30 min of ischemia and 60 min of reperfusion. In hearts from preconditioned rats we measured the activity of NOX2; the mRNA of Nrf2, gamma-glutamylcysteine ligase, glutathione dehydrogenase, thioredoxin reductase and sulfiredoxin by RT-qPCR; the content of glutathione; the activation of the NLRP3 inflammasome and the content of IL-1ß and IL-10 in cardiac tissue. In exosomes isolated from plasma, we quantified NOX2 activity. Results: The infarct size after IR decreased from 40% in controls to 9% of the heart volume after RIPC. This protective effect was lost in the presence of both inhibitors. RIPC increased NOX2 activity in the heart and exosomes, as indicated by the increased association of p47phox to the membrane and by the increased oxidation rate of NADPH. RIPC also increased the mRNA of Nrf2 and antioxidant enzymes. Also, RIPC increased the content of glutathione and the GSH/GSSG ratio. The inflammasome proteins NLRP3, procaspase-1, and caspase-1 were all increased in the hearts of RIPC rats. At the end of RIPC protocol, IL-1ß increased in plasma but decreased in cardiac tissue. At the same time, IL-10 did not change in cardiac tissue but increased by 70% during the next 50 min of perfusion. Conclusion: RIPC activates NOX2 which upregulates the heart's antioxidant defenses and activates the NLRP3 inflammasome which stimulates a cardiac anti-inflammatory response. These changes may underlie the decrease in the infarct size induced by RIPC.

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is one of the most complex and most prevalent cardiometabolic diseases in aging population. Age, obesity, diabetes, and hypertension are the main comorbidities of HFpEF. Microvascular dysfunction and vascular remodeling play a major role in its development. Among the many mechanisms involved in this process, vascular stiffening has been described as one the most prevalent during HFpEF, leading to ventricular-vascular uncoupling and mismatches in aged HFpEF patients. Aged blood vessels display an increased number of senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). This is consistent with the fact that EC and cardiomyocyte cell senescence has been reported during HFpEF. Autophagy plays a major role in VSMCs physiology, regulating phenotypic switch between contractile and synthetic phenotypes. It has also been described that autophagy can regulate arterial stiffening and EC and VSMC senescence. Many studies now support the notion that targeting autophagy would help with the treatment of many cardiovascular and metabolic diseases. In this review, we discuss the mechanisms involved in autophagy-mediated vascular senescence and whether this could be a driver in the development and progression of HFpEF.

Assuntos

Insuficiência Cardíaca , Humanos , Células Endoteliais , Volume Sistólico , Autofagia , Miócitos Cardíacos

RESUMO

The complex physiology of eukaryotic cells requires that a variety of subcellular organelles perform unique tasks, even though they form highly dynamic communication networks. In the case of the endoplasmic reticulum (ER) and mitochondria, their functional coupling relies on the physical interaction between their membranes, mediated by domains known as mitochondria-ER contacts (MERCs). MERCs act as shuttles for calcium and lipid transfer between organelles, and for the nucleation of other subcellular processes. Of note, mounting evidence shows that they are heterogeneous structures, which display divergent behaviors depending on the cell type. Furthermore, MERCs are plastic structures that remodel according to intra- and extracellular cues, thereby adjusting the function of both organelles to the cellular needs. In consonance with this notion, the malfunction of MERCs reportedly contributes to the development of several age-related disorders. Here, we integrate current literature to describe how MERCs change, starting from undifferentiated cells, and their transit through specialization, malignant transformation (i.e., dedifferentiation), and aging/senescence. Along this journey, we will review the function of MERCs and their relevance for pivotal cell types, such as stem and cancer cells, cardiac, skeletal, and smooth myocytes, neurons, leukocytes, and hepatocytes, which intervene in the progression of chronic diseases related to age.

RESUMO

Hypertension is associated with high circulating angiotensin II (Ang II). We have reported that autophagy regulates Ang II-induced vascular smooth muscle cell (VSMC) hypertrophy, but the mechanism mediating this effect is still unknown. Therefore, we studied how Ang II regulates LC3 levels in VSMCs and whether Bag3, a co-chaperone known to regulate LC3 total levels, may be involved in the effects elicited by Ang II. A7r5 cell line or rat aortic smooth muscle cell (RASMC) primary culture were stimulated with Ang II 100 nM for 24 h and LC3 I, LC3 II and Bag3 protein levels were determined by Western blot. MAP1LC3B mRNA levels were assessed by RT-qPCR. Ang II increased MAP1LC3B mRNA levels and protein levels of LC3 I, LC3 II and total LC3 (LC3 I + LC3 II). Cycloheximide, but not actinomycin D, abolished LC3 II and total LC3 increase elicited by Ang II in RASMCs. In A7r5 cells, cycloheximide prevented the Ang II-mediated increase of LC3 I and total LC3, but not LC3 II. Moreover, Ang II increased Bag3 levels, but this increase was not observed upon co-administration with either losartan 1 µM (AT1R antagonist) or Y-27632 10 µM (ROCK inhibitor). These results suggest that Ang II may regulate total LC3 content through transcriptional and translational mechanisms. Moreover, Bag3 is increased in response to Ang II by a AT1R/ROCK signalling pathway. These data provide preliminary evidence suggesting that Ang II may stimulate autophagy in VSMCs by increasing total LC3 content and LC3 processing.

Assuntos

Angiotensina II , Músculo Liso Vascular , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Cicloeximida/metabolismo , Cicloeximida/farmacologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , RNA Mensageiro/genética , Ratos

RESUMO

Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7-9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.

Assuntos

Cardiomiopatia Dilatada , Insuficiência Cardíaca , Rim Policístico Autossômico Dominante , Canais de Cátion TRPP , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cardiomiopatia Dilatada/patologia , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Rim Policístico Autossômico Dominante/genética , Isoformas de Proteínas/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo

RESUMO

Despite important advances in the treatment of myocardial infarction that have significantly reduced mortality, there is still an unmet need to limit the infarct size after reperfusion injury in order to prevent the onset and severity of heart failure. Multiple cardioprotective maneuvers, therapeutic targets, peptides and drugs have been developed to effectively protect the myocardium from reperfusion-induced cell death in preclinical studies. Nonetheless, the translation of these therapies from laboratory to clinical contexts has been quite challenging. Comorbidities, comedications or inadequate ischemia/reperfusion experimental models are clearly identified variables that need to be accounted for in order to achieve effective cardioprotection studies. The aging heart is characterized by altered proteostasis, DNA instability, epigenetic changes, among others. A vast number of studies has shown that multiple therapeutic strategies, such as ischemic conditioning phenomena and protective drugs are unable to protect the aged heart from myocardial infarction. In this Mini-Review, we will provide an updated state of the art concerning potential new cardioprotective strategies targeting the aging heart.

RESUMO

Despite considerable improvements in the treatment of myocardial infarction, it is still a highly prevalent disease worldwide. Novel therapeutic strategies to limit infarct size are required to protect myocardial function and thus, avoid heart failure progression. Cardioprotection is a research topic with significant achievements in the context of basic science. However, translation of the beneficial effects of protective approaches from bench to bedside has proven difficult. Therefore, there is still an unmet need to study new avenues leading to protecting the myocardium against infarction. In line with this, the endothelium is an essential component of the cardiovascular system with multiple therapeutic targets with cardioprotective potential. Endothelial cells are the most abundant non-myocyte cell type in the heart and are key players in cardiovascular physiology and pathophysiology. These cells can regulate vascular tone, angiogenesis, hemostasis, and inflammation. Accordingly, endothelial dysfunction plays a fundamental role in cardiovascular diseases, which may ultimately lead to myocardial infarction. The endothelium is of paramount importance to protect the myocardium from ischemia/reperfusion injury via conditioning strategies or cardioprotective drugs. This review will provide updated information on the most promising therapeutic agents and protective approaches targeting endothelial cells in the context of myocardial infarction.

RESUMO

En 31 de diciembre del 2019 la Organización Mundial de la Salud fue informada por las autoridades sanitarias chinas de la aparición de casos de neumonía de origen desconocido en la ciudad de Wuhan en China. El 7 de Enero de 2020, científicos chinos identificaron a un nuevo coronavirus (temporalmente designado como "2019-nCoV") como el agente etiológico de la enfermedad denominada COVID-19. La secuenciación del genoma del nuevo coronavirus mostró gran similitud con el coronavirus (Covid-1 o SARS-CoV) causante del síndrome respiratorio agudo severo (SARS), ocurrido también en China entre los años 2002-2003. Por este motivo, 2019-nCoV se rebautizó como SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus-2) y a la fecha es responsable de la actual y grave pandemia que está ocasionando impactos sanitarios y socio-económicos a escala global. Las investigaciones con SARS-CoV establecieron que este virus ingresa a nuestras células utilizando como receptor a la enzima convertidora de angiotensina tipo 2 (ECA 2 o en inglés ACE-2: "angiotensin converting enzyme type 2"). Dado este antecedente también se confirmó que SARS-CoV-2 también utiliza esta misma enzima ya que no se habla de un mecanismo en si para ingresar a sus células blanco, especialmente a nivel de nuestro sistema respiratorio. ECA-2 es una proteasa integrante del sistema renina angiotensina "alterno o no canónico" con importantes acciones regulatorias sobre los sistemas cardiovascular, renal y pulmonar, entre otros. En este contexto, ha surgido preocupación tanto por clínicos como los propios pacientes respecto al estado de pacientes hipertensos con COVID-19 y su vulnerabilidad a infectarse con SARS-CoV-2 dado que algunos trabajos han planteado que ciertos polimorfismos en el gen ECA-2 asociados a hipertensión arterial podrían determinar una mayor expresión de ECA-2. Además, estudios preclínicos han sugerido que ciertos fármacos antihipertensivos (principalmente, inhibidores de ECA y antagonistas del receptor para angiotensina II subtipo 1) también podrían estimular una mayor expresión de ECA-2. Esta revisión tiene por objetivo presentar y discutir los antecedentes en el estado del arte respecto a esta reciente problemática. El análisis crítico de los presentes antecedentes permite concluir que no existe evidencia clínica sólida que permita afirmar que el uso de medicamentos antihipertensivos genere una mayor vulnerabilidad a la infección con SARS-CoV-2. Por lo tanto no se debe descontinuar su uso en pacientes hipertensos en riesgo de infección a SARS-CoV-2 o que padezcan COVID-19.

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In December 2019, a new type of coronavirus emerged in the city of Wuhan, China. This novel virus has unleashed a pandemic that has inflicted a considerable impact on public health and the economy and has therefore become a severe concern worldwide. This new virus -named SARS-CoV-2has been rapidly investigated in order to create knowledge aimed at achieving its control. Comparative studies with SARS-CoV virus, responsible for the 2002-2003 pandemic, suggest that SARS-CoV-2 requires the same receptor to bind and infect cells: angiotensin converting enzyme 2 (ACE-2). This hypothesis has been thoroughly supported by a variety of in vitro research and is currently considered a potential therapeutic target. ACE-2 is part of the counter-regulatory renin-angiotensin system, exerting effects in pulmonary, renal and cardiovascular systems. In this context, concerns have arisen in regards to the vulnerability of hypertensive patients against COVID-19, given that there is evidence that may suggest that polymorphisms associated to hypertension may increase the expression of ACE-2. Moreover, preclinical studies have shown that antihypertensive drugs may increase the expression of this enzyme. In this review article, we present the current state of the art on this polemic topic. Our critical analysis suggest that there is no robust clinical evidence supporting the hypothesis that the use of antihypertensive drugs can increase vulnerability to infection with SARS-CoV-2. Therefore, we recommend that the use of these therapeutic agents should not be discontinued in hypertensive patients in risk to or suffering COVID-19.

Assuntos

Humanos , Pneumonia Viral/complicações , Infecções por Coronavirus/complicações , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pandemias , Betacoronavirus/metabolismo , Hipertensão/metabolismo

RESUMO

Cardiomyocyte loss is the main cause of myocardial dysfunction following an ischemia-reperfusion (IR) injury. Mitochondrial dysfunction and altered mitochondrial network dynamics play central roles in cardiomyocyte death. Proteasome inhibition is cardioprotective in the setting of IR; however, the mechanisms underlying this protection are not well-understood. Several proteins that regulate mitochondrial dynamics and energy metabolism, including Mitofusin-2 (Mfn2), are degraded by the proteasome. The aim of this study was to evaluate whether proteasome inhibition can protect cardiomyocytes from IR damage by maintaining Mfn2 levels and preserving mitochondrial network integrity. Using ex vivo Langendorff-perfused rat hearts and in vitro neonatal rat ventricular myocytes, we showed that the proteasome inhibitor MG132 reduced IR-induced cardiomyocyte death. Moreover, MG132 preserved mitochondrial mass, prevented mitochondrial network fragmentation, and abolished IR-induced reductions in Mfn2 levels in heart tissue and cultured cardiomyocytes. Interestingly, Mfn2 overexpression also prevented cardiomyocyte death. This effect was apparently specific to Mfn2, as overexpression of Miro1, another protein implicated in mitochondrial dynamics, did not confer the same protection. Our results suggest that proteasome inhibition protects cardiomyocytes from IR damage. This effect could be partly mediated by preservation of Mfn2 and therefore mitochondrial integrity.

Assuntos

GTP Fosfo-Hidrolases/metabolismo , Proteínas Mitocondriais/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Preparação de Coração Isolado , Masculino , Mitocôndrias/efeitos dos fármacos , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Cultura Primária de Células , Inibidores de Proteassoma/uso terapêutico , Ratos , Proteínas rho de Ligação ao GTP/metabolismo

RESUMO

The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II - initially thought to be biologically inactive - have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7, angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT2R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin-angiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

Assuntos

Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Sistema Renina-Angiotensina , Animais , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Humanos , Terapia de Alvo Molecular , Proto-Oncogene Mas , Sistema Renina-Angiotensina/efeitos dos fármacos

RESUMO

Acute myocardial infarction is one of the leading causes of death worldwide and thus, an extensively studied disease. Nonetheless, the effects of ischemia/reperfusion injury elicited by oxidative stress on cardiac fibroblast function associated with tissue repair are not completely understood. Ascorbic acid, deferoxamine, and N-acetylcysteine (A/D/N) are antioxidants with known cardioprotective effects, but the potential beneficial effects of combining these antioxidants in the tissue repair properties of cardiac fibroblasts remain unknown. Thus, the aim of this study was to evaluate whether the pharmacological association of these antioxidants, at low concentrations, could confer protection to cardiac fibroblasts against simulated ischemia/reperfusion injury. To test this, neonatal rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion in the presence or absence of A/D/N treatment added at the beginning of simulated reperfusion. Cell viability was assessed using trypan blue staining, and intracellular reactive oxygen species (ROS) production was assessed using a 2',7'-dichlorofluorescin diacetate probe. Cell death was measured by flow cytometry using propidium iodide. Cell signaling mechanisms, differentiation into myofibroblasts and pro-collagen I production were determined by Western blot, whereas migration was evaluated using the wound healing assay. Our results show that A/D/N association using a low concentration of each antioxidant increased cardiac fibroblast viability, but that their separate administration did not provide protection. In addition, A/D/N association attenuated oxidative stress triggered by simulated ischemia/reperfusion, induced phosphorylation of pro-survival extracellular-signal-regulated kinases 1/2 (ERK1/2) and PKB (protein kinase B)/Akt, and decreased phosphorylation of the pro-apoptotic proteins p38- mitogen-activated protein kinase (p38-MAPK) and c-Jun-N-terminal kinase (JNK). Moreover, treatment with A/D/N also reduced reperfusion-induced apoptosis, evidenced by a decrease in the sub-G1 population, lower fragmentation of pro-caspases 9 and 3, as well as increased B-cell lymphomaextra large protein (Bcl-xL)/Bcl-2-associated X protein (Bax) ratio. Furthermore, simulated ischemia/reperfusion abolished serum-induced migration, TGF-ß1 (transforming growth factor beta 1)-mediated cardiac fibroblast-to-cardiac myofibroblast differentiation, and angiotensin II-induced pro-collagen I synthesis, but these effects were prevented by treatment with A/D/N. In conclusion, this is the first study where a pharmacological combination of A/D/N, at low concentrations, protected cardiac fibroblast viability and function after simulated ischemia/reperfusion, and thereby represents a novel therapeutic approach for cardioprotection.

RESUMO

Resumen: Las enfermedades cardiovasculares y el cáncer son enfermedades crónicas transmisibles culturalmente, y las dos causas principales de mortalidad en el mundo. Además del gran impacto sobre la mortalidad y morbilidad, estas enfermedades han mostrado un alto grado de relación entre ellas debido, entre otras razones, a que comparten factores de riesgo y mecanismos biológicos. La alta incidencia de enfermedad cardiovascular en pacientes con cáncer es un fenómeno conocido que ha orientado el desarrollo del campo interdisciplinario de la cardio-oncología. Sin embargo, en la última década han surgido evidencias que muestran el papel que desempeñan las enfermedades cardiovasculares en el desarrollo de cáncer. Un estudio reciente publicado por Meijers y cols, en agosto de 2018 en Circulation, mostró que la insuficiencia cardiaca post-infarto del miocardio contribuye significativamente al desarrollo del cáncer de colón, apoyando lo obtenido en estudios epidemiológicos anteriores. Este estudio también sugiere que el crecimiento tumoral podría producirse por factores secretados por el corazón insuficiente abriendo un amplio grupo de posibilidades de investigación en lo que sería un nuevo campo de la medicina cuyo propósito sería el desarrollo de nuevas estrategias para el seguimiento y tratamiento del cáncer en pacientes con enfermedades cardiovasculares. El presente artículo revisa los factores de riesgo, y mecanismos celulares y moleculares, que son comunes en las enfermedades cardiovasculares y el cáncer, la contribución del trabajo de Meijers y cols hacia un mayor entendimiento de la interrelación entre estas patologías y las perspectivas futuras con respecto a los nuevos hallazgos.

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Abstracts: Cardiovascular diseases and cancer are culturally transmitted chronic diseases and the two main causes of death globally. In addition to their high morbidity and mortality, these diseases are closely related, due to their common risk factors and biological mechanisms. The high incidence of cardiovascular diseases in cancer patients is widely known phenomenon, which has oriented the development of the interdisciplinary field of cardio-oncology Nonetheless, there is emerging evidence in the last decade suggesting a potential role for cardiovascular diseases in the onset of cancer. A recent publication by Meijers et al in the scientific cardiovascular journal Circulation showed that heart failure significantly contributes to tumor growth, confirming previous epidemiological findings suggesting this hypothesis. Moreover, this study indicates that tumor growth may be stimulated by the secretion of factors from the failing heart, opening a wide spectrum of research areas in what may be suggested as a new field in medicine that would seek to develop new strategies to treat and prevent cancer in patients with cardiovascular diseases. This article will review shared risk factor and common cellular and molecular pathways in cardiovascular diseases and cancer, the contribution of Meijers et al to a better understanding of the connection of these diseases and future perspectives in light of the new evidence.

Assuntos

Humanos , Doenças Cardiovasculares/epidemiologia , Neoplasias/epidemiologia , Fatores de Risco , Insuficiência Cardíaca/epidemiologia

Assuntos

Doenças Cardiovasculares , Microbioma Gastrointestinal , Humanos

RESUMO

Angiotensin-(19), a peptide of the non-classical renin angiotensin system, has been shown to prevent and revert hypertension and cardiac hypertrophy. We hypothetized that systemic delivery of angiotensin-(1-9) following myocardial infarction will also be protective and extend to provide protection during reperfusion of the ischemic heart. Adult Sprague Dawley rats were subjected to left anterior descending artery ligation and treated with angiotensin-(1-9) via osmotic mini-pump for 2 weeks in the presence or absence of Mas receptor or AT2R antagonists (A779 and PD123319, respectively). Myocardial death and left ventricular function were evaluated after infarction. Infarct size and functional parameters were determined in isolated rat hearts after global ischemia/reperfusion in the presence of angiotensin-(1-9) plus receptor antagonists or Akt inhibitor at reperfusion. in vitro, neonatal rat ventricular cardiomyocytes underwent simulated ischemia/reperfusion and angiotensin-(1-9) was co-incubated with A779, PD123319 or Akt inhibitor. Systemic delivery of angiotensin-(1-9) significantly decreased cell death and improved left ventricular recovery after in vivo myocardial infarction. Perfusion with the peptide reduced the infarct size and improved functional recovery after ex vivo ischemia/reperfusion. In vitro, angiotensin-(1-9) decreased cell death in isolated neonatal rat ventricular cardiomyocytes subjected to simulated ischemia/reperfusion. The cardioprotective effects of angiotensin-(1-9) were blocked by PD123319 and Akti VIII but not by A779. Angiotensin-(1-9) limits reperfusion-induced cell death by an AT2R- and Aktdependent mechanism. Angiotensin-(1-9) is a novel strategy to protect against cardiac ischemia/reperfusion injury.

Assuntos

Angiotensina I/uso terapêutico , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Cardiotônicos/farmacologia , Células Cultivadas , Coração/efeitos dos fármacos , Coração/fisiologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo

RESUMO

Vascular smooth muscle cells (VSMC) dedifferentiation from a contractile to a synthetic phenotype contributes to atherosclerosis. Atherosclerotic tissue has a chronic inflammatory component with high levels of tumor necrosis factor-α (TNF-α). VSMC of atheromatous plaques have increased autophagy, a mechanism responsible for protein and intracellular organelle degradation. The aim of this study was to evaluate whether TNF-α induces phenotype switching of VSMCs and whether this effect depends on autophagy. Rat aortic Vascular smooth A7r5 cell line was used as a model to examine the phenotype switching and autophagy. These cells were stimulated with TNF-α 100 ng/mL. Autophagy was determined by measuring LC3-II and p62 protein levels. Autophagy was inhibited using chloroquine and siRNA Beclin1. Cell dedifferentiation was evaluated by measuring the expression of contractile proteins α-SMA and SM22, extracellular matrix protein osteopontin and type I collagen levels. Cell proliferation was measured by [3H]-thymidine incorporation and MTT assay, and migration was evaluated by wound healing and transwell assays. Expression of IL-1ß, IL-6 and IL-10 was assessed by ELISA. TNF-α induced autophagy as determined by increased LC3-II (1.91±0.21, p<0.001) and decreased p62 (0.86±0.02, p<0.05) when compared to control. Additionally, TNF-α decreased α-SMA (0.74±0.12, p<0.05) and SM22 (0.54±0.01, p<0.01) protein levels. Consequently, TNF-α induced migration (1.25±0.05, p<0.05), proliferation (2.33±0.24, p<0.05), and the secretion of IL-6 (258±53, p<0.01), type I collagen (3.09±0.85, p<0.01) and osteopontin (2.32±0.46, p<0.01). Inhibition of autophagy prevented all the TNF-α-induced phenotypic changes. TNF-α induces phenotype switching in A7r5 cell line by a mechanism that required autophagy. Therefore, autophagy may be a potential therapeutic target for the treatment of atherosclerosis.

Assuntos

Aterosclerose/metabolismo , Autofagia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Aterosclerose/patologia , Linhagem Celular , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Ratos

RESUMO

Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.

Assuntos

Arritmias Cardíacas/etiologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/complicações , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Disfunção Ventricular/etiologia , Acetofenonas/uso terapêutico , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , NADPH Oxidase 4/metabolismo , Obesidade/etiologia , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular/tratamento farmacológico

RESUMO

Hypertension is a disease associated to increased plasma levels of angiotensin II (Ang II). Ang II can regulate proliferation, migration, ROS production and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanisms by which Ang II can affect VSMCs remain to be fully elucidated. In this context, autophagy, a process involved in self-digestion of proteins and organelles, has been described to regulate vascular remodeling. Therefore, we sought to investigate if Ang II regulates VSMC hypertrophy through an autophagy-dependent mechanism. To test this, we stimulated A7r5 cell line and primary rat aortic smooth muscle cells with Ang II 100 nM and measured autophagic markers at 24 h by Western blot. Autophagosomes were quantified by visualizing fluorescently labeled LC3 using confocal microscopy. The results showed that treatment with Ang II increases Beclin-1, Vps34, Atg-12-Atg5, Atg4 and Atg7 protein levels, Beclin-1 phosphorylation, as well as the number of autophagic vesicles, suggesting that this peptide induces autophagy by activating phagophore initiation and elongation. These findings were confirmed by the assessment of autophagic flux by co-administering Ang II together with chloroquine (30 µM). Pharmacological antagonism of the angiotensin type 1 receptor (AT1R) with losartan and RhoA/Rho Kinase inhibition prevented Ang II-induced autophagy. Moreover, Ang II-induced A7r5 hypertrophy, evaluated by α-SMA expression and cell size, was prevented upon autophagy inhibition. Taking together, our results suggest that the induction of autophagy by an AT1R/RhoA/Rho Kinase-dependent mechanism contributes to Ang II-induced hypertrophy in VSMC.