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BACKGROUND: Substantial evidence embraced the nutrition competence of the Mediterranean diet (MD) as a healthy model for decreasing the risk of chronic diseases and increasing longevity, with the bonus of ensuring environmental sustainability. Measuring adherence to this diet is marginally investigated in the Arabian Gulf region, an area away from the Mediterranean region. The current study aimed to assess the MD adherence among adults in Sharjah/the United Arab Emirates (UAE), and to identify the most influential predictors for MD adherence among the study participants. METHODS: A cross-sectional study design was employed using a self-reported, web-based electronic questionnaire that questioned sociodemographics, lifestyle factors, and familiarity with the MD. The MD adherence was assessed by the Mediterranean Diet Adherence Screener validated questionnaire. The adherence level was classified as low for a total score of [0-5], medium [score 6-7], and high (8-13). RESULTS: The study included 1314 participants (age 25-52 years) comprised 822 (62.6%) females and 492 (37.4%) males. There was a moderate adherence score (5.9 ± 1.9) among the study participants. The food constituent expressed the lowest contribution to the MD was fish (9.3%), followed by fruits (12.3%), and legumes (18.3%). The multivariable linear regression analysis showed an overall significant linear trend for the association between the MD adherence score and physical activity, while nutrition information from dietitians and social media were the most two strongly related predictors for the higher adherence (ß = 0.747; 95% CI 0.51-0.98, and ß 0.60; 95% CI 0.269-0.93; p < 0.001, respectively). On the other side, being a smoker and from a non-Mediterranean country was associated with lower adherence scores (ß = 0.538; 95% CI 0.252-0.82, p < 0.001). CONCLUSION: The findings of the current study showed a moderate adherence, low proportion for high adherence, and a gap in the familiarity with the diet name. Being married, physically active, non-smoker, and getting nutrition information from dietitians and social media were the strongest predictors for higher adherence. It is warranted that public health and nutrition specialists/dietitians to tailor new modern approaches for promoting healthy dietary behaviours consistent with the MD.
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Dieta Mediterránea , Humanos , Emiratos Árabes Unidos , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Adulto , Cooperación del Paciente/estadística & datos numéricos , Encuestas y Cuestionarios , Estilo de Vida , Conducta AlimentariaRESUMEN
BACKGROUND: The use of induction immunosuppression for heart transplantation (HT) is debated given the uncertain benefit and potential risks of infection and malignancy. METHODS: This is a retrospective single-center analysis of 475 consecutive HT recipients from 2003 to 2020 grouped by use of induction with basiliximab group (BG) and the no basiliximab group (NBG). Subgroup analysis by era compared pre-2016 standard-basiliximab (BX) induction and 2016-2020 with selective-BX use as part of a calcineurin-inhibitor-sparing regimen. RESULTS: When adjusted for confounders (sex, age, PRA, eGFR), the BG was less likely to have acute cellular rejection (ACR) (OR.42, p < .001), but had more antibody mediated rejection (AMR) (OR 11.7, p < .001) and more cardiac allograft vasculopathy (CAV) (OR 3.8, p = .04). There was no difference between BG and NBG in the incidence of malignancies or infections. When stratified by era (pre-2016 vs. 2016-2020), ACR remained less common in the BG than the NBG (36% vs. 50%, p = .045) groups, while AMR remained more common (9.7 vs. 0% p = .005). There was no significant difference in conditional survival comparing pre-and post-2016 NBG (HR 2.20 (95% CI.75-6.43); however, both pre-2016 BG and post-2016 BG have significantly higher mortality (HR 2.37 [95% CI 1.02-5.50) and HR 2.69 (95% CI 1.08-6.71), p = .045 and.03, respectively]. CONCLUSION: Basiliximab reduces the incidence of ACR but increases the risk of AMR, CAV, and may be associated with increased mortality. Mechanistic studies are needed to describe a potential T-cell-escape mechanism with enhanced humoral immunity.
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Trasplante de Corazón , Neoplasias , Humanos , Basiliximab/uso terapéutico , Inmunosupresores/uso terapéutico , Inmunosupresores/farmacología , Anticuerpos Monoclonales/uso terapéutico , Estudios Retrospectivos , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Trasplante de Corazón/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
The instability of anthocyanins limits their application in food supplementation and in the food industry. Stabilities of strawberry anthocyanins (AN) were improved by complexation with both ß-CD and starch against heat, H2O2, light, and UV irradiation. The stability of AN against H2O2 (2.21 mM) dropped (<20%) in 6 h but was enhanced in ß-CD (49.32%) and starch (96.84%) complexes. Under light conditions, AN in the solid and solution (3.88 g/100 mL) forms degraded to 36.49 and 11.11%, while ß-CD and starch complexes displayed stabilities of 98.20 and 91.76%, respectively, after 60 days. Under UV irradiation, AN showed similar instability where both AN forms expressed stabilities of 36.75 and 66.18%, respectively, after 168 h, while ß-CD and starch complexes exhibited 51.13 and 40.10%, respectively. LC-MS-ESI showed that photoirradiation of both destroyed the full conjugation of the flavylium ring of the major components, pelargonidin and cyanidin hexoses; the mechanism was proposed. Docking binding models of major AN components in ß-CD were obtained.
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BACKGROUND: Previous retrospective studies suggest a good diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/computed tomography (CT) in left ventricular assist device (LVAD) infections. Our aim was to prospectively evaluate the role of PET/CT in the characterization and impact on clinical management of LVAD infections. METHODS: A total of 40 patients (aged 58 [53-62] years) with suspected LVAD infection and 5 controls (aged 69 [64-71] years) underwent 18F-FDG-PET/CT. Four LVAD components were evaluated: exit site and subcutaneous driveline (peripheral), pump pocket, and outflow graft. The location with maximal uptake was considered the presumed site of infection. Infection was confirmed by positive culture (exit site or blood) and/or surgical findings. RESULTS: Visual uptake was present in 40 patients (100%) in the infection group vs 4 (80%) control subjects. For each individual component, the presence of uptake was more frequent in the infection than in the control group. The location of maximal uptake was most frequently the pump pocket (48%) in the infection group and the peripheral components (75%) in the control group. Maximum standard uptake values (SUVmax) were higher in the infection than in the control group: SUVmax (average all components): 6.9 (5.1-8.5) vs 3.8 (3.7-4.3), p = 0.002; SUVmax (location of maximal uptake): 10.6 ± 4.0 vs 5.4 ± 1.9, p = 0.01. Pump pocket infections were more frequent in patients with bacteremia than without bacteremia (79% vs 31%, p = 0.011). Pseudomonas (32%) and methicillin-susceptible Staphylococcus aureus (29%) were the most frequent pathogens and were associated with pump pocket infections, while Staphylococcus epidermis (11%) was associated with peripheral infections. PET/CT affected the clinical management of 83% of patients with infection, resulting in surgical debridement (8%), pump exchange (13%), and upgrade in the transplant listing status (10%), leading to 8% of urgent transplants. CONCLUSIONS: 18F-FDG-PET/CT enables the diagnosis and characterization of the extent of LVAD infections, which can significantly affect the clinical management of these patients.
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Bacteriemia , Corazón Auxiliar , Infecciones Relacionadas con Prótesis , Humanos , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Corazón Auxiliar/efectos adversos , Tomografía Computarizada por Rayos X , Estudios Retrospectivos , Infecciones Relacionadas con Prótesis/diagnóstico por imagen , Infecciones Relacionadas con Prótesis/etiología , Bacteriemia/diagnóstico , Bacteriemia/etiologíaRESUMEN
PURPOSE OF REVIEW: Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. It has a wide spectrum of clinical manifestations including aortic regurgitation (AR), aortic stenosis, and an associated aortopathy with a small but increased risk of aortic dissection. This review describes current knowledge of BAV, from anatomy and genetics to a discussion of multifaceted strategies utilized in the management of this unique patient population. This review will also highlight critical knowledge gaps in areas of basic and clinical research to enhance further understanding of this clinical entity. RECENT FINDINGS: The current knowledge regarding pathophysiologic mechanisms, screening, and surveillance guidelines for BAV and the associated aortopathy is discussed. We also discuss current management techniques for aortic valve repair versus replacement, indications for aortic surgery (root or ascending aorta), and the emergence of the Ross procedure as a viable management option not only in children, but also in adolescents and adults. The varied clinical phenotype of the BAV, resulting in its specific complex hemodynamic interactions, renders it an entity which is separate and distinct from the tricuspid aortic valve pathologies. While various aortic histopathologic and protein alterations in BAV patients have been described, it remains unclear if these changes are causal or the result of hemodynamic alterations imposed by sheer stress on the intrinsically dysfunctional BAV. Medical management for patients with BAV with AS, AI, or dilated aortic roots/ascending aortas remains challenging and needs further investigation. More than 50% of patients with BAV will undergo AVR during their lifetime, and more than 25% of patients with BAV undergo aortic surgery performed for dilation of the aortic root or ascending aorta, often concurrently with AVR. The search for the ultimate genetic or epigenetic cause of the different bicuspid phenotypes will ultimately be facilitated by the next-generation sequencing tools that allow for study of large populations at low cost. Improvements in diagnostic and stratification criteria to accurately risk assess BAV patients are critical to this process.
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Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Enfermedades de las Válvulas Cardíacas , Válvula Aórtica/patología , Insuficiencia de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/cirugía , Dilatación Patológica/patología , Dilatación Patológica/cirugía , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/cirugía , HumanosRESUMEN
Imaging is central to the care of patients with infective endocarditis. Although transthoracic and transesophageal echocardiography are the principal imaging techniques, additional modalities including positron emission tomography and cardiac computed tomography, and to a lesser extent intracardiac echocardiography, play an increasing role. This review discusses the role of cardiac imaging in establishing the diagnosis of endocarditis, in predicting its embolic risk, and in making decisions regarding the need for and timing of surgery.
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Endocarditis Bacteriana , Endocarditis , Prótesis Valvulares Cardíacas , Ecocardiografía/métodos , Ecocardiografía Transesofágica , Endocarditis/diagnóstico por imagen , Endocarditis Bacteriana/diagnóstico por imagen , HumanosRESUMEN
Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Prolapso de la Válvula Mitral , Adulto , Ecocardiografía , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/epidemiología , Femenino , Humanos , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/epidemiología , Masculino , Prolapso de la Válvula Mitral/diagnóstico por imagen , Prolapso de la Válvula Mitral/epidemiologíaRESUMEN
During the coronavirus disease 2019 (COVID-19) pandemic, strained acute care resources, the potential for rapid clinical decompensation, and concerns about staff safety has prompted a conservative management approach for acute coronary syndrome patients. We present our experience of COVID-19 patients at Elmhurst Hospital Center presenting with ST-Elevation Myocardial Infarction and compared outcomes of invasive vs conservative treatment strategies.
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COVID-19/epidemiología , Angiografía Coronaria/métodos , Manejo de la Enfermedad , Pandemias , Intervención Coronaria Percutánea/métodos , Medición de Riesgo/métodos , Infarto del Miocardio con Elevación del ST/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Infarto del Miocardio con Elevación del ST/epidemiología , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data. OBJECTIVES: This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19. METHODS: We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization. RESULTS: A total of 305 patients were included. Mean age was 63 years and 205 patients (67.2%) were male. Overall, myocardial injury was observed in 190 patients (62.3%). Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions. Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities. Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities. CONCLUSIONS: Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury. Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present.
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Infecciones por Coronavirus/diagnóstico por imagen , Corazón/diagnóstico por imagen , Miocardio/patología , Neumonía Viral/diagnóstico por imagen , Disfunción Ventricular/virología , Anciano , Betacoronavirus , Biomarcadores/sangre , COVID-19 , Angiografía Coronaria , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/mortalidad , Ecocardiografía , Electrocardiografía , Femenino , Corazón/fisiopatología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Estudios Retrospectivos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
There is a desperate search to discover effective therapies against coronavirus disease-2019 (COVID-19). Patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) comprise a unique population whose clinical course may provide insights into the effects of antiretroviral therapy on COVID-19. We describe the case of a patient with HIV/AIDS on left ventricular assist device support who was hospitalized and recovered from COVID-19. (Level of Difficulty: Intermediate.).
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RATIONALE: LonP1 is an essential mitochondrial protease, which is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. However, the importance of LonP1 during cardiac stress is largely unknown. OBJECTIVE: To determine the functions of LonP1 during ischemia/reperfusion (I/R) injury in vivo, and hypoxia-reoxygenation (H/R) stress in vitro. METHODS AND RESULTS: LonP1 was induced 2-fold in wild-type mice during cardiac ischemic preconditioning (IPC), which protected the heart against ischemia-reperfusion (I/R) injury. In contrast, haploinsufficiency of LonP1 (LONP1+/-) abrogated IPC-mediated cardioprotection. Furthermore, LONP1+/- mice showed significantly increased infarct size after I/R injury, whereas mice with 3-4 fold cardiac-specific overexpression of LonP1 (LonTg) had substantially smaller infarct size and reduced apoptosis compared to wild-type controls. To investigate the mechanisms underlying cardioprotection, LonTg mice were subjected to ischemia (45â¯min) followed by short intervals of reperfusion (10, 30, 120â¯min). During early reperfusion, the left ventricles of LonTg mice showed substantially reduced oxidative protein damage, maintained mitochondrial redox homeostasis, and showed a marked downregulation of both Complex I protein level and activity in contrast to NTg mice. Conversely, when LonP1 was knocked down in isolated neonatal rat ventricular myocytes (NRVMs), an up-regulation of Complex I subunits and electron transport chain (ETC) activities was observed, which was associated with increased superoxide production and reduced respiratory efficiency. The knockdown of LonP1 in NRVMs caused a striking dysmorphology of the mitochondrial inner membrane, mitochondrial hyperpolarization and increased hypoxia-reoxygenation (H/R)-activated apoptosis. Whereas, LonP1 overexpression blocked H/R-induced cell death. CONCLUSIONS: LonP1 is an endogenous mediator of cardioprotection. Our findings show that upregulation of LonP1 mitigates cardiac injury by preventing oxidative damage of proteins and lipids, preserving mitochondrial redox balance and reprogramming bioenergetics by reducing Complex I content and activity. Mechanisms that promote the upregulation of LonP1 could be beneficial in protecting the myocardium from cardiac stress and limiting I/R injury.
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Proteasas ATP-Dependientes/genética , Proteínas Mitocondriales/genética , Infarto del Miocardio/genética , Estrés Oxidativo/genética , Daño por Reperfusión/genética , Animales , Animales Recién Nacidos , Apoptosis/genética , Complejo I de Transporte de Electrón/genética , Regulación de la Expresión Génica/genética , Precondicionamiento Isquémico Miocárdico , Lípidos/genética , Ratones , Mitocondrias/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Especies Reactivas de Oxígeno , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Superóxidos/metabolismoRESUMEN
The valosin-containing protein (VCP) participates in signaling pathways essential for cell homeostasis in multiple tissues, however, its function in the heart in vivo remains unknown. Here we offer the first description of the expression, function and mechanism of action of VCP in the mammalian heart in vivo in both normal and stress conditions. By using a transgenic (TG) mouse with cardiac-specific overexpression (3.5-fold) of VCP, we demonstrate that VCP is a new and powerful mediator of cardiac protection against cell death in vivo, as evidenced by a 50% reduction of infarct size after ischemia/reperfusion versus wild type. We also identify a novel role of VCP in preserving mitochondrial respiration and in preventing the opening of mitochondrial permeability transition pore in cardiac myocytes under stress. In particular, by genetic deletion of inducible isoform of nitric oxide synthase (iNOS) from VCP TG mouse and by pharmacological inhibition of iNOS in isolated cardiac myocytes, we reveal that an increase of expression and activity of iNOS in cardiomyocytes by VCP is an essential mechanistic link of VCP-mediated preservation of mitochondrial function. These data together demonstrate that VCP may represent a novel therapeutic avenue for the prevention of myocardial ischemia.
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Respiración de la Célula , Supervivencia Celular , Mitocondrias/metabolismo , Miocardio/metabolismo , Proteína que Contiene Valosina/metabolismo , Adenosina Difosfato/metabolismo , Animales , Biomarcadores , Respiración de la Célula/genética , Supervivencia Celular/genética , Femenino , Eliminación de Gen , Expresión Génica , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Modelos Biológicos , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Consumo de Oxígeno , Proteína que Contiene Valosina/genéticaRESUMEN
OBJECTIVES: Stress-inducible heat shock protein 22 (Hsp22) confers protection against ischemia through induction of the inducible isoform of nitric oxide synthase (iNOS). Hsp22 overexpression in vivo stimulates cardiac mitochondrial respiration, whereas Hsp22 deletion in vivo significantly reduces respiration. We hypothesized that Hsp22-mediated regulation of mitochondrial function is dependent upon its mitochondrial translocation together with iNOS. METHODS AND RESULTS: Adenoviruses harboring either the full coding sequence of Hsp22 (Ad-WT-Hsp22) or a mutant lacking a N-terminal 20 amino acid putative mitochondrial localization sequence (Ad-N20-Hsp22) were generated, and infected in rat neonatal cardiomyocytes. Compared to ß-Gal control, WT-Hsp22 accumulated in mitochondria by 2.5 fold (P<0.05) and increased oxygen consumption rates by 2-fold (P<0.01). This latter effect was abolished upon addition of the selective iNOS inhibitor, 1400 W. Ad-WT-Hsp22 significantly increased global iNOS expression by about 2.5-fold (P<0.01), and also increased iNOS mitochondrial localization by 4.5 fold vs. ß-gal (P<0.05). Upon comparable overexpression, the N20-Hsp22 mutant did not show significant mitochondrial translocation or stimulation of mitochondrial respiration. Moreover, although N20-Hsp22 did increase global iNOS expression by 4.6-fold, it did not promote iNOS mitochondrial translocation. CONCLUSION: Translocation of both Hsp22 and iNOS to the mitochondria is necessary for Hsp22-mediated stimulation of oxidative phosphorylation.
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Proteínas del Choque Térmico HSP20/fisiología , Mitocondrias Cardíacas/metabolismo , Proteínas Musculares/fisiología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Células Cultivadas , Proteínas de Choque Térmico , Masculino , Ratones , Ratones Transgénicos , Mitocondrias Cardíacas/enzimología , Membranas Mitocondriales/metabolismo , Chaperonas Moleculares , Fosforilación Oxidativa , Transporte de Proteínas , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Expression of the heat shock protein 22 (Hsp22) in the heart stimulates cardiac cell survival through activation of the Akt pathway and expression of the inducible nitric oxide (NO) synthase (iNOS), the mediator of ischaemic preconditioning and the most powerful prophylaxis against cardiac cell death. The goal of the present study was to elucidate the downstream effector by which Hsp22 and Akt increase iNOS expression. We tested both in vivo and in vitro the hypothesis that such an effector is the valosin-containing protein (VCP), an Akt substrate, which activates the transcription factor NF-κB, using a transgenic mouse with cardiac-specific over-expression of Hsp22, as well as isolated rat cardiac myocytes. METHODS AND RESULTS: Using two-dimensional gel electrophoresis and mass spectrometry combined with immunoprecipitation, we found that Hsp22 and Akt co-localize and interact together with VCP. Adeno-mediated over-expression of VCP in isolated cardiac myocytes activated NF-κB and dose-dependently increased the expression of iNOS, which was abolished upon NF-κB inhibition. Over-expression of a dominant-negative (DN) mutant of VCP did not increase iNOS expression. VCP, but not its DN mutant, protected against chelerythrine-induced apoptosis, which was suppressed by inhibition of either NF-κB or iNOS. VCP-mediated activation of the NF-κB/iNOS pathway was also prevented upon inhibition of Akt. CONCLUSION: We conclude that the Akt substrate, VCP, mediates the increased expression of iNOS downstream from Hsp22 through an NF-κB-dependent mechanism.
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Adenosina Trifosfatasas/fisiología , Proteínas de Ciclo Celular/fisiología , Miocitos Cardíacos/fisiología , Óxido Nítrico Sintasa de Tipo II/fisiología , Adenosina Trifosfatasas/análisis , Animales , Proteínas de Ciclo Celular/análisis , Supervivencia Celular , Células Cultivadas , Proteínas del Choque Térmico HSP20/fisiología , Proteínas de Choque Térmico , Isoenzimas/fisiología , Masculino , Ratones , Chaperonas Moleculares , Proteínas Musculares/fisiología , Miocitos Cardíacos/citología , FN-kappa B/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Ratas , Ratas Sprague-Dawley , Proteína que Contiene ValosinaRESUMEN
BACKGROUND: Cardiac overload, a major cause of heart failure, induces the expression of the heat shock protein H11 kinase/Hsp22 (Hsp22). METHODS AND RESULTS: To determine the specific function of Hsp22 in that context, a knockout mouse model of Hsp22 deletion was generated. Although comparable to wild-type mice in basal conditions, knockout mice exposed to pressure overload developed less hypertrophy and showed ventricular dilation, impaired contractile function, increased myocyte length and accumulation of interstitial collagen, faster transition into heart failure, and increased mortality. Microarrays revealed that hearts from knockout mice failed to transactivate genes regulated by the transcription factor STAT3. Accordingly, nuclear STAT3 tyrosine phosphorylation was decreased in knockout mice. Silencing and overexpression experiments in isolated neonatal rat cardiomyocytes showed that Hsp22 activates STAT3 via production of interleukin-6 by the transcription factor nuclear factor-κB. In addition to its transcriptional function, STAT3 translocates to the mitochondria where it increases oxidative phosphorylation. Both mitochondrial STAT3 translocation and respiration were also significantly decreased in knockout mice. CONCLUSIONS: This study found that Hsp22 represents a previously undescribed activator of both nuclear and mitochondrial functions of STAT3, and its deletion in the context of pressure overload in vivo accelerates the transition into heart failure and increases mortality.
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Eliminación de Gen , Proteínas del Choque Térmico HSP20/genética , Insuficiencia Cardíaca/genética , Mitocondrias Cardíacas/genética , Proteínas Musculares/genética , Factor de Transcripción STAT3/genética , Animales , Cardiomegalia/enzimología , Cardiomegalia/genética , Núcleo Celular/enzimología , Núcleo Celular/genética , Células Cultivadas , Colágeno/metabolismo , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/mortalidad , Proteínas de Choque Térmico , Interleucina-6/biosíntesis , Masculino , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/enzimología , Chaperonas Moleculares , Miocitos Cardíacos/enzimología , FN-kappa B/metabolismo , Fosforilación Oxidativa , RatasRESUMEN
AIMS: The regulation of protein degradation by the proteasome during cardiac hypertrophy remains largely unknown. Also, the proteasome translocates to the nuclear periphery in response to cellular stress in yeast, which remains unexplored in mammals. The purpose of this study was to determine the quantitative and qualitative adaptation of the proteasome during stable cardiac hypertrophy. METHODS AND RESULTS: We measured proteasome activity, expression and sub-cellular distribution in a model of chronic cardiac hypertrophy induced by the stress-response chaperone H11 Kinase/Hsp22 (Hsp22). Over-expression of Hsp22 in a transgenic (TG) mouse leads to a 30% increase in myocyte cross-sectional area compared to wild-type (WT) mice (P < 0.01). Characterization of the proteasome in hearts from TG mice vs. WT revealed an increased expression of both 19S and 20S subunits (P < 0.05), a doubling in 20S catalytic activity (P < 0.01), a redistribution of both subunits from the cytosol to the nuclear periphery, and a four-fold increase in nuclear-associated 20S catalytic activity (P < 0.001). The perinuclear proteasome co-localized and interacted with Hsp22. Inhibition of proteasome activity by epoxomicin reduced hypertrophy in TG by 50% (P < 0.05). Adeno-mediated over-expression of Hsp22 in isolated cardiac myocytes increased both cell growth and proteasome activity, and both were prevented upon inhibition of the proteasome. Similarly, stimulation of cardiac cell growth by pro-hypertrophic stimuli increased Hsp22 expression and proteasome activity, and proteasome inhibition in that setting prevented hypertrophy. Proteasome inhibitors also prevented the increase in rate of protein synthesis observed after over-expression of Hsp22 or upon addition of pro-hypertrophic stimuli. CONCLUSIONS: Hsp22-mediated cardiac hypertrophy promotes an increased expression and activity, and a subcellular redistribution of the proteasome. Inhibition of the proteasome reverses cardiac hypertrophy upon Hsp22 over-expression or upon stimulation by pro-hypertrophic hormones, and also blocks the stimulation of protein synthesis in these conditions.
Asunto(s)
Cardiomegalia/etiología , Proteínas del Choque Térmico HSP20/fisiología , Proteínas Musculares/fisiología , Complejo de la Endopetidasa Proteasomal/fisiología , Animales , Cardiomegalia/enzimología , Cardiomegalia/prevención & control , Proliferación Celular , Activación Enzimática , Proteínas de Choque Térmico , Ratones , Ratones Transgénicos , Chaperonas Moleculares , Inhibidores de ProteasomaRESUMEN
H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac-specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol-3-kinase/Akt pathway, the AMP-dependent protein kinase, the PKCepsilon pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage.