RESUMO
Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake and fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations in numerous cardiovascular functional parameters, including blood pressure, heart rate, and myocardial contractility. It is, therefore, not surprising that metabolic processes also fluctuate over the course of the day, to ensure temporal needs for ATP, building blocks, and metabolism-based signaling molecules are met. What has become increasingly clear is that in addition to classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks to temporally orchestrate metabolic pathways in preparation for predicted stimuli/stresses (termed anticipatory mechanisms). Here, we review current knowledge regarding circadian regulation of metabolism, how metabolic rhythms are synchronized with cardiovascular function, and whether circadian misalignment/disruption of metabolic processes contribute toward the pathogenesis of cardiovascular disease.
Assuntos
Relógios Circadianos , Ritmo Circadiano , Coração , Relógios Circadianos/fisiologia , Sono/fisiologia , Miocárdio/metabolismoRESUMO
Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.
Assuntos
Relógios Circadianos , Demência Vascular , Acidente Vascular Cerebral , Humanos , Ritmo Circadiano , Sono/fisiologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Relógios Circadianos/fisiologiaRESUMO
Ischemia/reperfusion (I/R) injury after revascularization contributes â¼50% of infarct size and causes heart failure, for which no established clinical treatment exists. ß-hydroxybutyrate (ß-OHB), which serves as both an energy source and a signaling molecule, has recently been reported to be cardioprotective when administered immediately before I/R and continuously after reperfusion. This study aims to determine whether administering ß-OHB at the time of reperfusion with a single dose can alleviate I/R injury and, if so, to define the mechanisms involved. We found plasma ß-OHB levels were elevated during ischemia in STEMI patients, albeit not to myocardial protection level, and decreased after revascularization. In mice, compared with normal saline, ß-OHB administrated at reperfusion reduced infarct size (by 50%) and preserved cardiac function, as well as activated autophagy and preserved mtDNA levels in the border zone. Our treatment with one dose ß-OHB reached a level achievable with fasting and strenuous physical activity. In neonatal rat ventricular myocytes (NRVMs) subjected to I/R, ß-OHB at physiologic level reduced cell death, increased autophagy, preserved mitochondrial mass, function, and membrane potential, in addition to attenuating reactive oxygen species (ROS) levels. ATG7 knockdown/knockout abolished the protective effects of ß-OHB observed both in vitro and in vivo. Mechanistically, ß-OHB's cardioprotective effects were associated with inhibition of mTOR signaling. In conclusion, ß-OHB, when administered at reperfusion, reduces infarct size and maintains mitochondrial homeostasis by increasing autophagic flux (potentially through mTOR inhibition). Since ß-OHB has been safely tested in heart failure patients, it may be a viable therapeutic to reduce infarct size in STEMI patients.
Assuntos
Insuficiência Cardíaca , Traumatismo por Reperfusão Miocárdica , Infarto do Miocárdio com Supradesnível do Segmento ST , Camundongos , Ratos , Animais , Humanos , Masculino , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Mitocôndrias/metabolismo , Autofagia , Serina-Treonina Quinases TOR/metabolismo , Reperfusão , Insuficiência Cardíaca/metabolismoRESUMO
On Earth, all life is exposed to dramatic changes in the environment over the course of the day; consequently, organisms have evolved strategies to both adapt to and anticipate these 24-h oscillations. As a result, time of day is a major regulator of mammalian physiology and processes, including transcription, signaling, metabolism, and muscle contraction, all of which oscillate over the course of the day. In particular, the heart is subject to wide fluctuations in energetic demand throughout the day as a result of waking, physical activity, and food intake patterns. Daily rhythms in cardiovascular function ensure that increased delivery of oxygen, nutrients, and endocrine factors to organs during the active period and the removal of metabolic by-products are in balance. Failure to maintain these physiologic rhythms invariably has pathologic consequences. This review highlights rhythms that underpin cardiac physiology. More specifically, we summarize the key aspects of cardiac physiology that oscillate over the course of the day and discuss potential mechanisms that regulate these 24-h rhythms.
Assuntos
Ritmo Circadiano/fisiologia , Coração/fisiologia , Animais , Fenômenos Fisiológicos Cardiovasculares , Fenômenos Cronobiológicos , HumanosRESUMO
OBJECTIVE: To describe a craniectomy using a lateral, transzygomatic approach to the middle fossa and rostral brainstem, and to report clinical outcomes and complications in three dogs. ANIMALS: Two cadaver dogs and three client-owned dogs. Two of the client-owned dogs with middle fossa lesions, and one with a rostral brainstem lesion. METHODS: Two cadavers were used to describe the lateral, transzygomatic surgical approach to the middle fossa and rostral brainstem. The medical records of three dogs undergoing this surgical approach were reviewed for data on signalment, preoperative and postoperative neurological status, diagnostic imaging, surgical technique, complications, and outcome. RESULTS: Indications for this surgical approach included incisional biopsy (n = 1) and debulking surgery for brain lesions (n = 2). Definitive diagnoses were achieved in two cases, and tumor volume reduction in all cases. Two of the three dogs developed postoperative facial nerve paralysis ipsilateral to the surgical site, which resolved within 2 and 12 weeks after surgery. CONCLUSION: The lateral, transzygomatic approach provided useful access to ventrally located cerebral/skull base lesions in dogs without major complications.
Assuntos
Craniotomia , Base do Crânio , Humanos , Cães , Animais , Base do Crânio/cirurgia , Craniotomia/veterináriaRESUMO
Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m2) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Endométrio , Neoplasias Pulmonares , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/uso terapêuticoRESUMO
An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24-hours day, in association with diurnal sleep-wake and fasting-feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day-night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet-induced obesity disrupts cardiac "diurnal metabolic flexibility", which is normalized by time-of-day-restricted feeding. Chronic high fat feeding (20-wk)-induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24-hours rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day-night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day-night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18-wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12-hours dark (active) phase, for a 2-wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day-night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for nonoxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity-induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.
Assuntos
Ritmo Circadiano/fisiologia , Miocárdio/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Essentially all biological processes fluctuate over the course of the day, observed at cellular (eg, transcription, translation, and signaling), organ (eg, contractility and metabolism), and whole-body (eg, physical activity and appetite) levels. It is, therefore, not surprising that both cardiovascular physiology (eg, heart rate and blood pressure) and pathophysiology (eg, onset of adverse cardiovascular events) oscillate during the 24-hour day. Chronobiological influence over biological processes involves a complex interaction of factors that are extrinsic (eg, neurohumoral factors) and intrinsic (eg, circadian clocks) to cells. Here, we focus on circadian governance of 6 fundamentally important processes: metabolism, signaling, electrophysiology, extracellular matrix, clotting, and inflammation. In each case, we discuss (1) the physiological significance for circadian regulation of these processes (ie, the good); (2) the pathological consequence of circadian governance impairment (ie, the bad); and (3) whether persistence/augmentation of circadian influences contribute to pathogenesis during distinct disease states (ie, the ugly). Finally, the translational impact of chronobiology on cardiovascular disease is highlighted.
Assuntos
Relógios Biológicos , Doenças Cardiovasculares/etiologia , Fenômenos Fisiológicos Cardiovasculares , Animais , Humanos , Miocárdio/metabolismoRESUMO
Essentially all biological processes fluctuate over the course of the day, manifesting as time-of-day-dependent variations with regards to the way in which organ systems respond to normal behaviors. For example, basic, translational, and epidemiologic studies indicate that temporal partitioning of metabolic processes governs the fate of dietary nutrients, in a manner in which concentrating caloric intake towards the end of the day is detrimental to both cardiometabolic and cardiovascular parameters. Despite appreciation that branched chain amino acids impact risk for obesity, diabetes mellitus, and heart failure, it is currently unknown whether the time-of-day at which dietary BCAAs are consumed influence cardiometabolic/cardiovascular outcomes. Here, we report that feeding mice a BCAA-enriched meal at the end of the active period (i.e., last 4 h of the dark phase) rapidly increases cardiac protein synthesis and mass, as well as cardiomyocyte size; consumption of the same meal at the beginning of the active period (i.e., first 4 h of the dark phase) is without effect. This was associated with a greater BCAA-induced activation of mTOR signaling in the heart at the end of the active period; pharmacological inhibition of mTOR (through rapamycin) blocked BCAA-induced augmentation of cardiac mass and cardiomyocyte size. Moreover, genetic disruption of the cardiomyocyte circadian clock abolished time-of-day-dependent fluctuations in BCAA-responsiveness. Finally, we report that repetitive consumption of BCAA-enriched meals at the end of the active period accelerated adverse cardiac remodeling and contractile dysfunction in mice subjected to transverse aortic constriction. Thus, our data demonstrate that the timing of BCAA consumption has significant implications for cardiac health and disease.
Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Metabolismo Energético , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Vigília , Fatores de Transcrição ARNTL/deficiência , Animais , Biomarcadores , Relógios Circadianos , Suscetibilidade a Doenças , Ingestão de Alimentos , Camundongos , Camundongos Knockout , Biossíntese de Proteínas , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Remodelação Ventricular/genéticaRESUMO
Background A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registration www.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.
Assuntos
Antineoplásicos/uso terapêutico , Carbolinas/uso terapêutico , Doxorrubicina/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbolinas/administração & dosagem , Carbolinas/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de ProgressãoRESUMO
Primary leiomyosarcoma of the fallopian tube is a very rare neoplasm with descriptions limited to case reports. We present the case of a 46-yr-old woman with a history of renal transplantation in whom a primary leiomyosarcoma of the fallopian tube was identified incidentally following hysterectomy and bilateral salpingectomy undertaken for a uterine fibroid. The tumor demonstrated classic morphological and immunohistochemical features of a leiomyosarcoma. It appeared localized to the fallopian tube and was completely resected. Adjuvant therapy was not given but active surveillance initiated. After 14 mo of follow-up, there was no evidence of disease recurrence. We review cases from the past 20 yr with a focus on management and outcomes. Given the rarity of this disease, continued publication of case reports and the creation of a centralized case registry would be of benefit.
Assuntos
Neoplasias das Tubas Uterinas/diagnóstico , Leiomioma/diagnóstico , Leiomiossarcoma/diagnóstico , Intervalo Livre de Doença , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/cirurgia , Tubas Uterinas/patologia , Feminino , Humanos , Histerectomia , Hospedeiro Imunocomprometido , Leiomioma/patologia , Leiomiossarcoma/patologia , Leiomiossarcoma/cirurgia , Pessoa de Meia-Idade , SalpingectomiaRESUMO
OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an essential tool in the diagnosis of pancreatic lesions. The aim of this study was to evaluate the diagnostic accuracy of cytology from EUS-FNA, to correlate the results with the corresponding histopathological diagnoses and to analyse the impact of retrospective assignment of the Papanicolaou Society of Cytopathology (PSC) reporting system categories. METHODS: All pancreatic FNA specimens reported at the Royal Free Hospital during a 2-year period were retrospectively collected and assigned to the PSC system categories. Any available corresponding histological samples were assessed for concordance. RESULTS: In total, 236 cytology specimens from 223 patients were identified, of which 108 (45.8%) had corresponding histology samples. The main reason for cyto-histological discrepancy was sampling error. Interpretive error was identified in one case. Overall, sensitivity was 92.5%, specificity was 100%, diagnostic accuracy of cytology was 95%, false-positive rate was 0% and false-negative rate was 7.5%. The implementation of the new reporting system reduced the number of cases in the atypical category. All cases previously categorised as suspicious or malignant remained in the same category. CONCLUSIONS: EUS-FNA is an accurate method for evaluating pancreatobiliary lesions. The implementation of the Papanicolaou Society of Cytopathology diagnostic system enhances standardisation of the reporting terminology and reduces the number of samples in the non-standardised and equivocal atypical category.
Assuntos
Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Técnicas Citológicas/métodos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sociedades Médicas , Adulto JovemRESUMO
Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes.
Assuntos
Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal , Insuficiência Cardíaca/microbiologia , Insuficiência Cardíaca/fisiopatologia , Animais , Proteínas CLOCK/metabolismo , Hemodinâmica , Inflamação/patologia , Leucócitos/patologia , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/microbiologia , Infarto do Miocárdio/fisiopatologia , Remodelação Ventricular/fisiologiaRESUMO
The mechanisms which underlie defects in learning and memory are a major area of focus with the increasing incidence of Alzheimer's disease in the aging population. The complex genetically-controlled, age-, and environmentally-dependent onset and progression of the cognitive deficits and neuronal pathology call for better understanding of the fundamental biology of the nervous system function. In this study, we focus on nuclear receptor binding factor-2 (NRBF2) which modulates the transcriptional activities of retinoic acid receptor α and retinoid X receptor α, and the autophagic activities of the BECN1-VPS34 complex. Since both transcriptional regulation and autophagic function are important in supporting neuronal function, we hypothesized that NRBF2 deficiency may lead to cognitive deficits. To test this, we developed a new mouse model with nervous system-specific knockout of Nrbf2. In a series of behavioral assessment, we demonstrate that NRBF2 knockout in the nervous system results in profound learning and memory deficits. Interestingly, we did not find deficits in autophagic flux in primary neurons and the autophagy deficits were minimal in the brain. In contrast, RNAseq analyses have identified altered expression of genes that have been shown to impact neuronal function. The observation that NRBF2 is involved in learning and memory suggests a new mechanism regulating cognition involving the role of this protein in regulating networks related to the function of retinoic acid receptors, protein folding, and quality control.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Encéfalo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Especificidade de Órgãos/genética , Transativadores/genética , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Transativadores/metabolismoRESUMO
Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day-1·mouse-1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment.NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.
Assuntos
Antioxidantes/farmacologia , Insuficiência Cardíaca/metabolismo , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Modelos Animais de Doenças , Camundongos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Oxirredução/efeitos dos fármacos , RNA não Traduzido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/farmacologiaRESUMO
Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/ß; BMAL1 induces REV-ERBα/ß, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/ß expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/ß activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/ß agonist SR-9009 (100 mg·kg-1·day-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3ß signaling). Collectively, these observations highlight a role for REV-ERBα/ß as a mediator of a subset of circadian clock-controlled processes in the heart.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Miocárdio/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Fatores de Transcrição ARNTL/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Coração/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Pirrolidinas/farmacologia , Tiofenos/farmacologiaRESUMO
AIMS: The FDA-approved histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been shown to induce cardiomyocyte autophagy and blunt ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, the precise mechanisms underlying the cardioprotective activity of SAHA are unknown. Mitochondrial dysfunction and oxidative damage are major contributors to myocardial apoptosis during I/R injury. We hypothesize that SAHA protects the myocardium by maintaining mitochondrial homeostasis and reducing reactive oxygen species (ROS) production during I/R injury. METHODS: Mouse and cultured cardiomyocytes (neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes) I/R models were used to investigate the effects of SAHA on mitochondria. ATG7 knockout mice, ATG7 knockdown by siRNA and PGC-1α knockdown by adenovirus in cardiomyocytes were used to test the dependency of autophagy and PGC-1α-mediated mitochondrial biogenesis respectively. RESULTS: Intact and total mitochondrial DNA (mtDNA) content and mitochondrial mass were significantly increased in cardiomyocytes by SAHA pretreatment before simulated I/R. In vivo, I/R induced >50% loss of mtDNA content in the border zones of mouse hearts, but SAHA pretreatment and reperfusion treatment alone reverted mtDNA content and mitochondrial mass to control levels. Moreover, pretreatment of cardiomyocytes with SAHA resulted in a 4-fold decrease in I/R-induced loss of mitochondrial membrane potential and a 25%-40% reduction in cytosolic ROS levels. However, loss-of-function of ATG7 in cardiomyocytes or mouse myocardium abolished the protective effects of SAHA on ROS levels, mitochondrial membrane potential, mtDNA levels, and mitochondrial mass. Lastly, PGC-1α gene expression was induced by SAHA in NRVMs and mouse heart subjected to I/R, and loss of PGC-1α abrogated SAHA's mitochondrial protective effects in cardiomyocytes. CONCLUSIONS: SAHA prevents I/R induced-mitochondrial dysfunction and loss, and reduces myocardial ROS production when given before or after the ischemia. The protective effects of SAHA on mitochondria are dependent on autophagy and PGC-1α-mediated mitochondrial biogenesis.
Assuntos
Morte Celular Autofágica , Cardiotônicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Vorinostat/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
The endoplasmic reticulum/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca2+ entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (crSTIM1-KO) results in age-dependent endoplasmic reticulum stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-wk-old crSTIM1-KO mice exhibited a significant reduction in both oxidative and nonoxidative glucose utilization. Consistent with the reduction in glucose utilization, expression of glucose transporter 4 and AMP-activated protein kinase phosphorylation were all reduced, whereas pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphorylation were increased, in crSTIM1-KO hearts. Despite similar rates of fatty acid oxidation in control and crSTIM1-KO hearts ex vivo, crSTIM1-KO hearts contained increased lipid/triglyceride content as well as increased fatty acid-binding protein 4, fatty acid synthase, acyl-CoA thioesterase 1, hormone-sensitive lipase, and adipose triglyceride lipase expression compared with control hearts, suggestive of a possible imbalance between fatty acid uptake and oxidation. Insulin-mediated alterations in AKT phosphorylation were observed in crSTIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wk crSTIM1-KO hearts, suggesting that these changes may initiate the subsequent metabolic dysfunction. These results demonstrate, for the first time, that cardiomyocyte STIM1 may play a key role in regulating cardiac metabolism. NEW & NOTEWORTHY Little is known of the physiological role of stromal interaction molecule 1 (STIM1) in the heart. Here, we demonstrate, for the first time, that hearts lacking cardiomyocyte STIM1 exhibit dysregulation of both cardiac glucose and lipid metabolism. Consequently, these results suggest a potentially novel role for STIM1 in regulating cardiac metabolism.
Assuntos
Metabolismo Energético , Glucose/metabolismo , Metabolismo dos Lipídeos , Miócitos Cardíacos/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ácido Graxo Sintase Tipo I/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Feminino , Transportador de Glucose Tipo 4/metabolismo , Masculino , Camundongos Knockout , Oxirredução , Fosforilação , Proteínas Quinases/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Esterol Esterase/metabolismo , Molécula 1 de Interação Estromal/deficiência , Molécula 1 de Interação Estromal/genética , Tioléster Hidrolases/metabolismoRESUMO
Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ETB) receptor functions to facilitate Na+ excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ETB-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na+ channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ETB receptors within the renal inner medulla.
Assuntos
Proteínas CLOCK/metabolismo , Rim/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Sódio na Dieta/metabolismo , Animais , Ritmo Circadiano/fisiologia , Endotelinas/metabolismo , Comportamento Alimentar/fisiologia , Masculino , Proteínas Circadianas Period/metabolismo , RatosRESUMO
Multiple metabolic pathways exhibit time-of-day-dependent rhythms that are controlled by the molecular circadian clock. We have shown that chronic alcohol is capable of altering the molecular clock and diurnal oscillations in several elements of hepatic glycogen metabolism ( 19 , 44 ). Herein, we sought to determine whether genetic disruption of the hepatocyte clock differentially impacts hepatic glycogen content in chronic alcohol-fed mice. Male hepatocyte-specific BMAL1 knockout (HBK) and littermate controls were fed control or alcohol-containing diets for 5 wk to alter hepatic glycogen content. Glycogen displayed a significant diurnal rhythm in livers of control genotype mice fed the control diet. While rhythmic, alcohol significantly altered the diurnal oscillation of glycogen in livers of control genotype mice. The glycogen rhythm was mildly altered in livers of control-fed HBK mice. Importantly, glycogen content was arrhythmic in livers of alcohol-fed HBK mice. Consistent with these changes in hepatic glycogen content, we observed that some glycogen and glucose metabolism genes were differentially altered by chronic alcohol consumption in livers of HBK and littermate control mice. Diurnal rhythms in glycogen synthase (mRNA and protein) were significantly altered by alcohol feeding and clock disruption. Alcohol consumption significantly altered Gck, Glut2, and Ppp1r3g rhythms in livers of control genotype mice, with diurnal rhythms of Pklr, Glut2, Ppp1r3c, and Ppp1r3g further disrupted (dampened or arrhythmic) in livers of HBK mice. Taken together, these findings show that chronic alcohol consumption and hepatocyte clock disruption differentially influence the diurnal rhythm of glycogen and various key glycogen metabolism-related genes in the liver. NEW & NOTEWORTHY We report that circadian clock disruption exacerbates alcohol-mediated alterations in hepatic glycogen. We observed differential responsiveness in diurnal rhythms of glycogen and glycogen metabolism genes and proteins in livers of hepatocyte-specific BMAL1 knockout and littermate control mice fed alcohol. Our findings provide new insights into potential mechanisms by which alcohol alters glycogen, an important energy source for liver and other organs.