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1.
Nat Commun ; 12(1): 1684, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33727534

RESUMEN

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.


Asunto(s)
Proteína Forkhead Box O1/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Metabolismo de los Lípidos , Contracción Miocárdica , Volumen Sistólico , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Secuencia Conservada , Eliminación de Gen , Células HEK293 , Insuficiencia Cardíaca/genética , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Fenotipo , Estabilidad Proteica , Proteolisis , Transcripción Genética , Ubiquitina-Proteína Ligasas/metabolismo
2.
Int Heart J ; 62(2): 407-415, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33678798

RESUMEN

Exercise preconditioning (EP) provides protective effects for acute cardiovascular stress; however, its mechanisms need to be further investigated. Autophagy is a degradation pathway essential for myocardium health. Therefore, we investigated whether intermittent myocardial ischemia-hypoxia affected Beclin1 and whether the changes in autophagy levels contribute to EP-induced early myocardial protective effects. Rats were trained on a treadmill using an EP model (four cycles of 10 minutes of running/10 minutes of rest). Exhaustive exercise (EE) was performed to induce myocardial injury. Cardiac troponin I (cTnI) and ischemia-hypoxia staining were used to evaluate myocardial injury and protection. Double-labeled immunofluorescence staining and western blot analysis were employed to examine related markers. EP attenuated the myocardial ischemic-hypoxic injury induced by EE. Compared with the control (C) group, the dissociations of Beclin1/Bcl-2 ratio and Beclin1 expression were both higher in all other groups. Compared with the C group, PI3KC3 and the LC3-II/LC3-I ratio were higher in all other groups, whereas LC3-II was higher in the EE and EEP + EE groups. p62 was higher in the EE group than in the C group but lower in the EEP + EE group than in the EE group. We concluded that EP increases Beclin1 via intermittent myocardial ischemia-hypoxia and induces autophagy, which exerts early myocardial protective effects and reduces the myocardial ischemic-hypoxic injury induced by exhaustive exercise.


Asunto(s)
Beclina-1/metabolismo , Isquemia Miocárdica/prevención & control , Miocardio/metabolismo , Condicionamiento Físico Animal/métodos , Animales , Autofagia , Western Blotting , Modelos Animales de Enfermedad , Masculino , Isquemia Miocárdica/fisiopatología , Miocardio/patología , Ratas , Ratas Sprague-Dawley
3.
Int Heart J ; 62(2): 445-447, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33731536

RESUMEN

Recessive mutations in the Myosin regulatory light chain 2 (MYL2) gene are the cause of an infantile-onset myopathy, associated with fatal myocardial disease of variable macromorphology. We here present the first Japanese family affected with recessive MYL2 myopathy. Affected siblings manifested typical features and the proband's autopsy findings were compatible with the diagnosis of noncompaction cardiomyopathy. The rapidly progressive clinical course of this recessive MYL2 cardiomyopathy highlights the crucial role of c-terminal tails in MYL2 protein in maintaining cardiac morphology and function.


Asunto(s)
Cardiomiopatías/genética , ADN/genética , Mutación , Miocardio/patología , Proteína de la Leucemia Promielocítica/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/metabolismo , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Humanos , Lactante , Miocardio/metabolismo , Linaje , Proteína de la Leucemia Promielocítica/metabolismo
4.
Aquat Toxicol ; 233: 105794, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662880

RESUMEN

Polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are environmental contaminants known to impact cardiac development, a key step in the embryonic development of most animals. To date, little is understood of the molecular mechanism driving the observed cardiac defects in exposed fishes. The literature shows PCB & TCDD derived cardiac defects are concurrent with, but not caused by, expression of cyp1A, due to activation of the aryl hydrocarbon receptor (AhR) gene activation pathway. However, in this study, detailed visualization of fish hearts exposed to PCBs and TCDD show that, in addition to a failure of cardiac looping in early heart development, the inner endocardial lining of the heart fails to maintain proper cell adhesion and tissue integrity. The resulting gap between the endocardium and myocardium in both zebrafish and Atlantic sturgeon suggested functional faults in endothelial adherens junction formation. Thus, we explored the molecular mechanism triggering cardiac defects using immunohistochemistry to identify the location and phosphorylation state of key regulatory and adhesion molecules. We hypothesized that PCB and TCDD activates AhR, phosphorylating Src, which then phosphorylates the endothelial adherens junction protein, VEcadherin. When phosphorylated, VEcadherin dimers, found in the endocardium and vasculature, separate, reducing tissue integrity. In zebrafish, treatment with PCB and TCDD contaminants leads to higher phosphorylation of VEcadherin in cardiac tissue suggesting that these cells have reduced connectivity. Small molecule inhibition of Src phosphorylation prevents contaminant stimulated phosphorylation of VEcadherin and rescues both cardiac function and gross morphology. Atlantic sturgeon hearts show parallels to contaminant exposed zebrafish cardiac phenotype at the tissue level. These data suggest that the mechanism for PCB and TCDD action in the heart is, in part, distinct from the canonical mechanism described in the literature and that cardiac defects are impacted by this nongenomic mechanism.


Asunto(s)
Embrión no Mamífero/efectos de los fármacos , Corazón/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/metabolismo , Animales , Sinergismo Farmacológico , Embrión no Mamífero/anomalías , Embrión no Mamífero/metabolismo , Desarrollo Embrionario/efectos de los fármacos , Corazón/embriología , Miocardio/metabolismo , Pez Cebra/crecimiento & desarrollo
5.
BMC Bioinformatics ; 22(1): 116, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33691629

RESUMEN

BACKGROUND: Correlation network analysis has become an integral tool to study metabolite datasets. Networks are constructed by omitting correlations between metabolites based on two thresholds-namely the r and the associated p-values. While p-value threshold settings follow the rules of multiple hypotheses testing correction, guidelines for r-value threshold settings have not been defined. RESULTS: Here, we introduce a method that allows determining the r-value threshold based on an iterative approach, where different networks are constructed and their network topology is monitored. Once the network topology changes significantly, the threshold is set to the corresponding correlation coefficient value. The approach was exemplified on: (i) a metabolite and morphological trait dataset from a potato association panel, which was grown under normal irrigation and water recovery conditions; and validated (ii) on a metabolite dataset of hearts of fed and fasted mice. For the potato normal irrigation correlation network a threshold of Pearson's |r|≥ 0.23 was suggested, while for the water recovery correlation network a threshold of Pearson's |r|≥ 0.41 was estimated. For both mice networks the threshold was calculated with Pearson's |r|≥ 0.84. CONCLUSIONS: Our analysis corrected the previously stated Pearson's correlation coefficient threshold from 0.4 to 0.41 in the water recovery network and from 0.4 to 0.23 for the normal irrigation network. Furthermore, the proposed method suggested a correlation threshold of 0.84 for both mice networks rather than a threshold of 0.7 as applied earlier. We demonstrate that the proposed approach is a valuable tool for constructing biological meaningful networks.


Asunto(s)
Redes y Vías Metabólicas , Miocardio/metabolismo , Solanum tuberosum/metabolismo , Riego Agrícola , Animales , Correlación de Datos , Conjuntos de Datos como Asunto , Ratones
6.
Nat Commun ; 12(1): 1771, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741943

RESUMEN

Single-cell RNA sequencing is a powerful tool to study developmental biology but does not preserve spatial information about tissue morphology and cellular interactions. Here, we combine single-cell and spatial transcriptomics with algorithms for data integration to study the development of the chicken heart from the early to late four-chambered heart stage. We create a census of the diverse cellular lineages in developing hearts, their spatial organization, and their interactions during development. Spatial mapping of differentiation transitions in cardiac lineages defines transcriptional differences between epithelial and mesenchymal cells within the epicardial lineage. Using spatially resolved expression analysis, we identify anatomically restricted expression programs, including expression of genes implicated in congenital heart disease. Last, we discover a persistent enrichment of the small, secreted peptide, thymosin beta-4, throughout coronary vascular development. Overall, our study identifies an intricate interplay between cellular differentiation and morphogenesis.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Corazón/embriología , Morfogénesis/genética , Miocardio/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Embrión de Pollo , Pollos , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Mesodermo/citología , Mesodermo/embriología , Mesodermo/metabolismo , Miocardio/citología
7.
Sci Rep ; 11(1): 4930, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654230

RESUMEN

Multiple Biomarkers have recently been shown to be elevated in COVID-19, a respiratory infection with multi-organ dysfunction; however, information regarding the prognostic value of cardiac biomarkers as it relates to disease severity and cardiac injury are inconsistent. The goal of this meta-analysis was to summarize the evidence regarding the prognostic relevance of cardiac biomarkers from data available in published reports. PubMed, Embase and Web of Science were searched from inception through April 2020 for studies comparing median values of cardiac biomarkers in critically ill versus non-critically ill COVID-19 patients, or patients who died versus those who survived. The weighted mean differences (WMD) and 95% confidence interval (CI) between the groups were calculated for each study and combined using a random effects meta-analysis model. The odds ratio (OR) for mortality based on cardiac injury was combined from studies reporting it. Troponin levels were significantly higher in COVID-19 patients who died or were critically ill versus those who were alive or not critically ill (WMD 0.57, 95% CI 0.43-0.70, p < 0.001). Additionally, BNP levels were also significantly higher in patients who died or were critically ill (WMD 0.45, 95% CI - 0.21-0.69, p < 0.001). Cardiac injury was independently associated with significantly increased odds of mortality (OR 6.641, 95% CI 1.26-35.1, p = 0.03). A significant difference in levels of D-dimer was seen in those who died or were critically ill. CK levels were only significantly higher in those who died versus those who were alive (WMD 0.79, 95% CI 0.25-1.33, p = 0.004). Cardiac biomarkers add prognostic value to the determination of the severity of COVID-19 and can predict mortality.


Asunto(s)
Biomarcadores/sangre , /diagnóstico , Miocardio/metabolismo , /epidemiología , Cardiología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/complicaciones , Creatina Quinasa/metabolismo , Enfermedad Crítica , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , L-Lactato Deshidrogenasa/metabolismo , Péptido Natriurético Encefálico/análisis , Fragmentos de Péptidos/análisis , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos
8.
Sci Rep ; 11(1): 4828, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649391

RESUMEN

Novel coronavirus disease (COVID-19) has led to a major public health crisis globally. Currently, myocardial damage is speculated to be associated with COVID-19, which can be seen as one of the main causes of death of patients with COVID-19. We therefore, aim to investigate the effects of COVID-19 disease on myocardial injury in hospitalized patients who have been tested positive for COVID-19 pneumonia in this study. A prospective study was conducted among 201 patients with COVID-19 in the Pakistan Military Hospital from April 1 to August 31, 2020, including non-critical cases and critical cases. COVID-19 patients were stratified as critical and non-critical according to the signs and symptoms severity; with those requiring intensive care and invasive mechanical ventilation as critical, and those did not requiring invasive mechanical ventilation as non-critical. A total of 201 COVID-19 patients with critical and non-critical categories presented with myocardial injury. All patients with myocardial injury had an elevation in CKMB and Troponin-I levels. Of these patients, 43.7% presented with new electrocardiography (ECG) changes, and ST depression was typically observed in 36.3% patients. In addition, 18.7% patients presented with abnormal echocardiography findings, with right ventricular dilatation and dysfunction commonly seen among critical group patients. Results analyzed by a logistic regression model showing COVID-19 direct contribution to myocardial injury in these patients. COVID-19 disease directly leads to cardiovascular damage among critical and non-critical patients. Myocardial injury is associated not only with abnormal ECG changes but also with myocardial dysfunction on echocardiography and more commonly observed among critical patients.


Asunto(s)
Ecocardiografía , Electrocardiografía , Lesiones Cardíacas , /metabolismo , Adulto , /complicaciones , /terapia , Cuidados Críticos , Femenino , Lesiones Cardíacas/sangre , Lesiones Cardíacas/etiología , Lesiones Cardíacas/fisiopatología , Lesiones Cardíacas/terapia , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Estudios Prospectivos , Índice de Severidad de la Enfermedad
9.
Mol Med Rep ; 23(2): 1, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33655326

RESUMEN

Angiotensin II (AngII) is a central signaling molecule of the renin­angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA­negative control or siRNA­MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit­8, flow cytometry and Transwell assays, respectively. Reverse transcription­quantitative PCR (RT­qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease­, apoptosis­ and oxidative stress­related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII­treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT­qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α­smooth muscle actin and Collagen I in AngII­treated H9C2 cells (P<0.05). Moreover, compared with AngII­treated cells, MMP3 knockdown significantly decreased Bcl­2 expression levels , but significantly increased caspase­3 and p53 expression levels in AngII­treated cells (P<0.05). Additionally, compared with AngII­treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII­treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis­ and oxidative stress­related genes, thus delaying MF progression.


Asunto(s)
Angiotensina II/farmacología , Apoptosis , Fibrosis/genética , Corazón/fisiopatología , Metaloproteinasa 3 de la Matriz/metabolismo , Angiotensina II/metabolismo , Animales , Movimiento Celular , Supervivencia Celular , Células Cultivadas , Fibrosis/inducido químicamente , Fibrosis/metabolismo , Fibrosis/fisiopatología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Ratas , Transducción de Señal
10.
Nucleic Acids Res ; 49(5): 2522-2536, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33561291

RESUMEN

Simultaneous dysregulation of multiple microRNAs (miRs) affects various pathological pathways related to cardiac failure. In addition to being potential cardiac disease-specific markers, miR-23b/27b/24-1 were reported to be responsible for conferring cardiac pathophysiological processes. In this study, we identified a conserved guanine-rich RNA motif within the miR-23b/27b/24-1 cluster that can form an RNA G-quadruplex (rG4) in vitro and in cells. Disruption of this intragenic rG4 significantly increased the production of all three miRs. Conversely, a G4-binding ligand tetrandrine (TET) stabilized the rG4 and suppressed miRs production in human and rodent cardiomyocytes. Our further study showed that the rG4 prevented Drosha-DGCR8 binding and processing of the pri-miR, suppressing the biogenesis of all three miRs. Moreover, CRISPR/Cas9-mediated G4 deletion in the rat genome aberrantly elevated all three miRs in the heart in vivo, leading to cardiac contractile dysfunction. Importantly, loss of the G4 resulted in reduced targets for the aforementioned miRs critical for normal heart function and defects in the L-type Ca2+ channel-ryanodine receptor (LCC-RyR) coupling in cardiomyocytes. Our results reveal a novel mechanism for G4-dependent regulation of miR biogenesis, which is essential for maintaining normal heart function.


Asunto(s)
G-Cuádruplex , MicroARNs/química , MicroARNs/metabolismo , Contracción Miocárdica/genética , Miocitos Cardíacos/metabolismo , Animales , Bencilisoquinolinas/farmacología , Sistemas CRISPR-Cas , Células Cultivadas , G-Cuádruplex/efectos de los fármacos , Regulación de la Expresión Génica , Miocardio/metabolismo , Miocitos Cardíacos/fisiología , Procesamiento Postranscripcional del ARN , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Ribonucleasa III/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo
11.
Life Sci ; 271: 119190, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33571518

RESUMEN

AIMS: This study aimed to investigate the relationship between ischemia- and reperfusion-induced arrhythmia and blood serum estrogen levels, myocardial estrogen receptor levels, antioxidant enzyme activities, and the effects of the estrogen receptor blocker, fulvestrant (ICI 182 780). MAIN METHODS: A total of 102 female Sprague-Dawley rats of different ages (2-3, 6-7, 14-15, and 20-21 months) were used in this study. Myocardial ischemia was produced by ligation of the descending branch of the left anterior descending coronary artery, and reperfusion was produced by releasing this artery. An electrocardiogram (ECG) and blood pressure were recorded for 6 min of ischemia and 6 min of reperfusion. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), estrogen receptor α (ERα), and estrogen receptor ß (ERß) in myocardial tissue and 17 beta-estradiol (E2) in blood serum were measured via enzyme-linked immunosorbent assay (ELISA). The results were compared using a Mann-Whitney U test, one-way analysis of variance (ANOVA), and a student's t-test. KEY FINDINGS: It is not the changes in serum estrogen levels but the decreasing myocardial estrogen receptors and antioxidant activities that could be responsible for the occurrence of more severe arrhythmia in response to reperfusion in older female rats. SIGNIFICANCE: The death rate due to a heart attack in younger men is higher than in women. However, it equalizes after the menopausal stage in women. In this study, the reason for the increasing sudden post-menopausal death rate in women was investigated experimentally.


Asunto(s)
Envejecimiento/metabolismo , Antioxidantes/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Receptores Estrogénicos/metabolismo , Fibrilación Ventricular/metabolismo , Envejecimiento/patología , Animales , Electrocardiografía/métodos , Femenino , Frecuencia Cardíaca/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Ratas , Ratas Sprague-Dawley , Fibrilación Ventricular/fisiopatología
12.
Ecotoxicol Environ Saf ; 213: 112040, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33610943

RESUMEN

Among different synthetic compounds copper (Cu) is persistently and frequently used as growth promoter, antibacterial, antifungal and antiparasitic agent and has become common environmental pollutant. Therefore, this study explores the cardio-toxic effects of control group (10 mg/kg bw Cu) and treatment group (125 and 250 mg/kg bw Cu), and it association with process of autophagy and metabolomics in myocardium of pigs kept in three different experimental treatments for a period of 80 days. The results of serum biochemical parameters showed a significantly increase in creatinine kinase (CK), creatine kinase-MB (CK-MB), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and aspartate aminotransferase (AST) in pigs exposed to 125 mg/kg bw and 250 mg/kg bw Cu. Meanwhile, the severe structural abnormalities in cardiomyocytes were found when exposed to 250 mg/kg Cu at day 80. In addition, the mRNA and proteins (Beclin1, ATG5 and LC3II) expression levels were significantly increased and p62 was significantly decreased in cardiomyocytes exposed to 250 mg/kg Cu at day 80 of the trial. Further, UPLC-QTOF/MS technique showed that 7 metabolites were up-regulated and 37 metabolites were down-regulated in cardiomyocytes after 250 mg/kg Cu treatment, with a principal impact on the metabolic pathways including glycerophospholipid metabolism, one carbon pool by folate, fatty acid elongation and fatty acid degradation, which were related to autophagy. Overall, our study identified the autophagy processes and metabolites in metabolic pathways in Cu-induced myocardium injury, which provided useful evidence of myocardium toxicity caused by Cu exposure via metabolomics and multiple bioanalytic methods.


Asunto(s)
Autofagia/efectos de los fármacos , Cobre/toxicidad , Contaminantes Ambientales/toxicidad , Corazón/efectos de los fármacos , Animales , Contaminantes Ambientales/metabolismo , Corazón/fisiología , Redes y Vías Metabólicas , Metabolómica , Miocardio/metabolismo , Porcinos
13.
Nat Commun ; 12(1): 1041, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589633

RESUMEN

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.


Asunto(s)
Regulación del Apetito/fisiología , Ejercicio Físico/fisiología , Conducta Alimentaria/fisiología , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/genética , Resistencia Física/fisiología , Adulto , Animales , Creatina Quinasa/sangre , Creatina Quinasa/genética , Regulación de la Expresión Génica , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Interleucina-10/sangre , Interleucina-10/genética , Interleucina-6/administración & dosificación , Leptina/sangre , Leptina/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Motivación/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Condicionamiento Físico Animal , Factores de Tiempo
14.
Biomed Res Int ; 2021: 9491615, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33521132

RESUMEN

Background: L-carnitine mediates the utilization of fatty acids and glucose in the myocardium. The potential of L-carnitine in managing dilated cardiomyopathy (DCM) in patients has been extensively reported, with additional benefits. Objective: This meta-analysis purposed to explore the clinical efficacy of L-carnitine therapy on DCM patients. Methods: We searched publications up to May 2020 from several databases including PubMed, Embase, Cochrane Library, Chinese Biomedical (CBM) database, Chinese Science and Technology Periodicals database (VIP), Chinese National Knowledge Infrastructure (CNKI) database, and Wanfang database. Subsequently, publications that met the inclusion criteria were systematically evaluated by two independent reviewers. Results: A total of 23 RCTs conducted in China with 1455 DCM patients were included in this study. In the meta-analysis, L-carnitine therapy was associated with a considerable improvement in the overall efficacy (RR = 1.28, 95% CI (1.21-1.36), P < 0.0001), left ventricular ejection fraction (LVEF) (MD = 6.16%, 95% CI (4.50, 7.83), P < 0.0001), and cardiac output (CO) (MD = 0.88 L/min, 95% CI (0.51, 1.25), P < 0.0001) as compared to the control group. Moreover, L-carnitine therapy significantly decreased left ventricular end-diastolic dimension (LVEDD) (MD = -2.53, 95% CI (-3.95, -1.12), P = 0.0005), brain natriuretic peptide (BNP) (SMD = -1.71 ng/L, 95% CI (-3.02, -0.40), P = 0.01), and the transforming growth factor-beta (TGF-ß1) (MD = -56.78 ng/L, 95% CI (-66.02, -47.53), P < 0.0001). Conclusions: L-carnitine potentially enhanced the therapeutic efficiency in DCM patients. Following weaknesses in the evidence due to low methodological quality and high clinical heterogeneity in the included studies, well-designed trials are recommended.


Asunto(s)
Cardiomiopatía Dilatada/tratamiento farmacológico , Carnitina/uso terapéutico , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Miocardio/metabolismo , Humanos , Péptido Natriurético Encefálico/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Riesgo , Volumen Sistólico , Factor de Crecimiento Transformador beta1/metabolismo , Función Ventricular Izquierda
15.
Medicine (Baltimore) ; 100(5): e23804, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592838

RESUMEN

BACKGROUND: The vast majority of previous studies focused on the relationship between 1 meridian and 1 organ, and the comparison and specificity between 2 meridians is rarely explored. Thus, the aim of this study is to compare the heat transport characteristics between 2 different meridians and the specificity between them will also be investigated. METHODS: The Lung and Heart meridians are chosen for comparison of 2 different meridians. We will enroll 120 subjects and divide them into the healthy control group, chronic obstructive pulmonary disease (COPD) group and healthy intervention group, in a 1:1:1 ratio. Infrared thermography (IRT) will be used to assess the heat transport characteristics of the Heart and Lung meridians. The specificity for the meridian-visceral association will be investigated by comparing the difference in heat transport characteristic between the Heart and Lung meridians in the healthy control group and COPD group. Meanwhile, moxibustion will be given to subjects in the Heart meridian and Lung meridian respectively in the healthy intervention group to verify the specificity for the surface-surface association. RESULTS: The primary outcomes will be the temperature of corresponding sites along the Heart and Lung meridians. CONCLUSION: This study will verify the specificity between different meridians by comparing the difference in heat transport characteristic. The findings will guide the selection of acupoints to optimize the therapeutic effect of acupuncture and help determine whether IRT could be used to assist in the diagnosis of COPD. ETHICS AND DISSEMINATION: The study has been approved by the Third Affiliated Hospital of Zhejiang Chinese Medical University (Approval No. ZSLL-KY-2019-001G-01). TRIAL REGISTRATION NUMBERS: NCT04046588.


Asunto(s)
Meridianos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Termografía , Adulto , Anciano , Transporte Biológico , Estudios de Casos y Controles , Femenino , Corazón , Calor , Humanos , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/terapia
16.
Nat Commun ; 12(1): 869, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33558521

RESUMEN

The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.


Asunto(s)
Canales Iónicos/metabolismo , Mecanotransducción Celular , Miocardio/metabolismo , Animales , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Calcio/metabolismo , Señalización del Calcio , Cardiomiopatías/metabolismo , Cardiomiopatías/fisiopatología , Eliminación de Gen , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Pruebas de Función Cardíaca , Homeostasis , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Especificidad de Órganos , Pirazinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tiadiazoles/metabolismo , Regulación hacia Arriba
17.
Life Sci ; 272: 119189, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33571516

RESUMEN

AIMS: Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS: EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAP rat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS: EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE: These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.


Asunto(s)
MicroARNs/genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/prevención & control , Animales , Apoptosis/genética , China , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Corazón/fisiología , Inflamación/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Pancreatitis/complicaciones , Pancreatitis/genética , Pancreatitis/metabolismo , Sustancias Protectoras/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética
18.
Life Sci ; 272: 119228, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33607150

RESUMEN

AIMS: The purpose of this study was to reveal the therapeutic efficacy and underlying mechanism of cannabinoid type 2 receptor agonist (AM1241) on myocardial ischemia-reperfusion injury (MIRI) in rats. MAIN METHODS: We established a rat myocardial ischemia/reperfusion (I/R) model and H9c2 hypoxia/reoxygenation (H/R) model. ELISA was used to determine the concentrations of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in plasma. EB/TTC staining was performed to observe the myocardial infarct size. Besides, the pathological changes of myocardial tissue were identified via H&E staining and Masson's trichrome staining. TUNEL assay was performed to examine myocardial apoptosis. Then, the protein expression of Pink1, Parkin and autophagy-related markers (Beclin-1, P62 and LC3) were detected by Western blot, and autophagy was evaluated by Mitotracker staining. KEY FINDINGS: The results of EB/TTC staining, H&E staining, Masson's trichrome staining and cardiac enzymes measuring showed that AM1241 treatment significantly diminished infarct size, the structural abnormalities and the activities of cardiac enzymes (cTnI, CK-MB, AST and LDH). AM1241 also significantly reduced the number of TUNEL-positive cells induced by I/R in a dose-dependent manner. Furthermore, AM1241 activated Pink1/Parkin signaling pathway and upregulated autophagy level. SIGNIFICANCE: AM1241 exerts a protective effect against MIRI in rats by inducing autophagy through the activation of Pink1/Parkin pathway.


Asunto(s)
Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cannabinoides/metabolismo , Cannabinoides/farmacología , Masculino , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo
19.
Methods Mol Biol ; 2261: 443-456, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33421007

RESUMEN

Western blotting is one of the most used techniques in research laboratories. It is popular because it is an easy way of semiquantifying protein amounts in different samples. In Western blotting, the most commonly used method for controlling the differences in the amount of protein loaded is to independently quantify housekeeping proteins (typically actin, GAPDH or tubulin). Another less commonly used method is total protein normalization using stains, such as Ponceau S or Coomassie Brilliant Blue, which stains all the proteins on the blots. A less commonly used but powerful total protein staining technique is stain-free normalization. The stain-free technology is able to detect total protein in a large linear dynamic range and has the advantage of allowing protein detection on the gel before transblotting. This chapter discusses the theory, advantages, and method used to do total protein quantification using stain-free gels for normalization of Western blots.


Asunto(s)
Western Blotting/normas , Electroforesis en Gel de Poliacrilamida/normas , Miocardio/metabolismo , Proteínas/análisis , Animales , Calibración , Ratones , Estándares de Referencia
20.
Methods Mol Biol ; 2261: 525-533, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33421012

RESUMEN

Clinical tissue archives represent an invaluable source of biological information. Formalin-fixed, paraffin-embedded (FFPE) tissue can be used for retrospective investigation of biomarkers of diseases and prognosis.Recently, the number of studies using proteome profiling of samples from clinical archives has markedly increased. However, the application of conventional quantitative proteomics technologies remains a challenge mainly due to the harsh fixation process resulting in protein cross-linking and protein degradation. In the present chapter, we demonstrate a protocol for label-free proteomic analysis of FFPE tissue prepared from human cardiac autopsies. The data presented here highlight the applicability and suitability of FFPE heart tissue for understanding the molecular mechanism of cardiac injury using a proteomics approach.


Asunto(s)
Fijadores/química , Formaldehído/química , Miocardio/metabolismo , Adhesión en Parafina , Proteínas/análisis , Proteoma , Proteómica , Fijación del Tejido , Autopsia , Cromatografía de Fase Inversa , Humanos , Espectrometría de Masas en Tándem
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