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1.
Eur Rev Med Pharmacol Sci ; 24(23): 12500-12509, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336769

RESUMO

OBJECTIVE: Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality. MATERIALS AND METHODS: The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed. RESULTS: This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress. CONCLUSIONS: This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.


Assuntos
/mortalidade , Síndrome da Liberação de Citocina/imunologia , Glutationa/metabolismo , Lesão Pulmonar Aguda/metabolismo , Fatores Etários , Antioxidantes/metabolismo , Apoptose , /metabolismo , Síndrome da Liberação de Citocina/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Glutationa/imunologia , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Macrófagos/imunologia , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/metabolismo , Obesidade/epidemiologia , Obesidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Fumar/epidemiologia , Fumar/metabolismo
2.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336773

RESUMO

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Miocardite/imunologia , /metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Fator Natriurético Atrial/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Glicoproteínas/uso terapêutico , Humanos , Hipóxia/metabolismo , Hipóxia/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Isquemia Miocárdica/metabolismo , Miocardite/metabolismo , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Oxigenoterapia , Respiração Artificial , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Inibidores da Tripsina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , alfa-Metiltirosina/uso terapêutico
3.
J Pharmacol Sci ; 144(4): 218-228, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070841

RESUMO

Myocardial ischemia initiates a chain of pathological conditions leading to cardiomyocyte death. Therefore, pharmacological treatment to stop ischemia-induced damage is necessary. Fibrates, have been reported to decrease inflammatory markers and to modulate the renin-angiotensin system (RAS). Our aim was to explore if clofibrate treatment, administered one week after myocardial event, decreases MI-induced cardiac damage. Wistar rats were assigned to: 1. Sham or 2. Coronary artery ligation (MI). Seven days after, rats were subdivided to receive vehicle (V) or clofibrate [100 mg/kg (C)] daily for 7 days. Blood samples and left ventricle were analyzed. RAS components [angiotensin II, angiotensin converting enzyme (ACE), and AT1-receptor] decreased in MI-C compared to MI-V, while [Ang-(1-7), bradykinin, ACE-2, and AT2-receptor] raised in response to clofibrate treatment. Oxidative stress markers increased in MI-V rats, a profile reverted in MI-C rats. Nitric oxide (NO) pathway (Akt, eNOS, and NO) exhibits a lower participation in MI-V, but clofibrate raised NO-pathway components and its production. MI-induced fibrosis and structural damage was also improved by clofibrate-treatment. In conclusion, clofibrate administration to 7 days MI-rats exerts an antioxidant, pro-vasodilator expression profile, and anti-fibrotic effect suggesting that PPARα activation can be considered a therapeutic target to improve cardiac condition posterior to ischemia.


Assuntos
Clofibrato/administração & dosagem , Clofibrato/farmacologia , Ventrículos do Coração/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Fibrose , Ventrículos do Coração/patologia , Masculino , Isquemia Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Fatores de Tempo
4.
Medicine (Baltimore) ; 99(43): e22893, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120837

RESUMO

Radical cystectomy is considered the standard treatment for patients with muscle-invasive bladder tumors and has high postoperative complication rates among urological surgeries. High-risk patients, defined as those ≥45 years of age with history of coronary artery disease, stroke, or peripheral artery disease or those ≥65 years of age, can have a higher incidence of cardiac complications. Therefore, we evaluated the incidence, risk factors, and outcomes of myocardial injury after non-cardiac surgery (MINS) in high-risk patients who underwent radical cystectomy.This retrospective observational study analyzed 248 high-risk patients who underwent radical cystectomy. MINS was defined as serum troponin I concentration ≥0.04 mg/L within postoperative 3 days. The risk factors for MINS were evaluated by multivariate logistic regression analysis. Postoperative outcomes were evaluated. The 1-year survival after radical cystectomy was also compared between patients who developed MINS (MINS group) and those who did not (non-MINS group) by Kaplan-Meier analysis.MINS occurred in 35 patients (14.1%). Multivariate logistic regression analysis showed that early diastolic transmitral filling velocity (E)/early diastolic septal mitral annular velocity (E') ratio (odds ratio = 1.102, 95% confidence interval [1.009-1.203], P = .031) and large volume blood transfusion (odds ratio = 2.745, 95% confidence interval [1.131-6.664], P = .026) were significantly associated with MINS in high-risk patients who underwent radical cystectomy. Major adverse cardiac events and 1-year mortality were significantly higher in the MINS group than in the non-MINS group (17.1% vs 6.1%, P = .035; 28.6% vs 12.7%, P = .021, respectively). Kaplan-Meier analysis showed significantly lower 1-year survival in the MINS group than in the non-MINS group (P = .010).MINS occurred in 14.1% of patients. High E/E' ratio and large volume blood transfusion were risk factors for MINS in high-risk patients who underwent radical cystectomy. Postoperative major adverse cardiac events and 1-year mortality were significantly higher in the MINS group than in the non-MINS group. Preoperative evaluation of risk factors for MINS may provide useful information to detect cardiovascular complications after radical cystectomy in high-risk patients.


Assuntos
Cistectomia/efeitos adversos , Isquemia Miocárdica/etiologia , Troponina I/sangue , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue/estatística & dados numéricos , Estudos de Casos e Controles , Cistectomia/mortalidade , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/metabolismo , Estadiamento de Neoplasias/métodos , Complicações Pós-Operatórias/epidemiologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/patologia
5.
Vasc Health Risk Manag ; 16: 353-365, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982263

RESUMO

Among the vast number of noncommunicable diseases encountered worldwide, cardiovascular diseases accounted for about 17.8 million deaths in 2017 and ischemic heart disease (IHD) remains the single-largest cause of death in countries across all income groups. Because conventional medications are not without shortcomings and patients still refractory to these medications, scientific investigation is ongoing to advance the management of IHD, and shows a great promise for better treatment modalities, but additional research can warrant improvement in terms of the quality of life of patients. Metabolic modulation is one promising strategy for the treatment of IHD, because alterations in energy metabolism are involved in progression of the disease. Therefore, the purpose of this review was to strengthen attention toward the use of metabolic modulators and to review the current level of knowledge on cardiac energy metabolic pathways.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Humanos , Mitocôndrias Cardíacas/metabolismo , Terapia de Alvo Molecular , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo
6.
Am J Physiol Regul Integr Comp Physiol ; 319(3): R347-R357, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755463

RESUMO

How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), P < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice (P < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).


Assuntos
Dieta Hiperlipídica , Ingestão de Energia/fisiologia , Homeostase/fisiologia , Isquemia Miocárdica/fisiopatologia , Miocárdio/metabolismo , Animais , Coração/fisiopatologia , Resistência à Insulina/fisiologia , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Obesidade/fisiopatologia
7.
Am J Physiol Heart Circ Physiol ; 319(3): H682-H693, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795177

RESUMO

An ischemic insult is accompanied by an acute increase in circulating fatty acid (FA) levels, which can induce adverse changes related to cardiac metabolism/energetics. Although chronic hyperlipidemia contributes to the pathogenesis of obesity-/diabetes-related cardiomyopathy, it is unclear how these hearts are affected by an acute high FA-load. We hypothesize that adaptation to chronic FA exposure enhances the obese hearts' ability to handle an acute high FA-load. Diet-induced obese (DIO) and age-matched control (CON) mouse hearts were perfused in the presence of low- or high FA-load (0.4 and 1.8 mM, respectively). Left ventricular (LV) function, FA oxidation rate, myocardial oxygen consumption, and mechanical efficiency were assessed, followed by analysis of myocardial oxidative stress, mitochondrial respiration, protein acetylation, and gene expression. Finally, ischemic tolerance was determined by examining LV functional recovery and infarct size. Under low-FA conditions, DIO hearts showed mild LV dysfunction, oxygen wasting, mechanical inefficiency, and reduced mitochondrial OxPhos. High FA-load increased FA oxidation rates in both groups, but this did not alter any of the above parameters in DIO hearts. In contrast, CON hearts showed FA-induced mechanical inefficiency, oxidative stress, and reduced OxPhos, as well as enhanced acetylation and activation of PPARα-dependent gene expression. While high FA-load did not alter functional recovery and infarct size in CON hearts, it increased ischemic tolerance in DIO hearts. Thus, this study demonstrates that acute FA-load affects normal and obese hearts differently and that chronically elevated circulating FA levels render the DIO heart less vulnerable to the disadvantageous effects of an acute FA-load.NEW & NOTEWORTHY An acute myocardial fat-load leads to oxidative stress, oxygen wasting, mechanical inefficiency, hyperacetylation, and impaired mitochondrial function, which can contribute to reduced ischemic tolerance. Following obesity/insulin resistance, hearts were less affected by a high fat-load, which subsequently also improved ischemic tolerance. This study highlights that an acute fat-load affects normal and obese hearts differently and that obesity renders hearts less vulnerable to the disadvantageous effects of an acute fat-load.


Assuntos
Cardiomiopatias/metabolismo , Dieta Hiperlipídica , Metabolismo Energético , Ácidos Graxos/metabolismo , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Obesidade/metabolismo , Adaptação Fisiológica , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miocárdio/patologia , Obesidade/etiologia , Obesidade/patologia , Obesidade/fisiopatologia , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Função Ventricular Esquerda
8.
PLoS One ; 15(8): e0236457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790682

RESUMO

Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (CardiacCRT+) were analyzed. CardiacCRT+ cardiomyocytes showed increased contractility and Ca2+ transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of CardiacCRT+ mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from CardiacCRT+ mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, CardiacCRT+ hearts showed less efficient cardiac function than sham control hearts due to an increased ATP production from glycolysis relative to glucose oxidation. During reperfusion, this inefficiency was reversed, with CardiacCRT+ hearts exhibiting better functional recovery and increased cardiac efficiency compared to sham control hearts. On the other hand, mechanical stretching of isolated cardiac fibroblasts activated the IRE1α branch of the unfolded protein response pathway as well as induction of Col1A2 and TGFß gene expression ex vivo, which were all suppressed by tauroursodeoxycholic acid.


Assuntos
Calreticulina/metabolismo , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Calreticulina/genética , Células Cultivadas , Metabolismo Energético , Frequência Cardíaca , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Isquemia Miocárdica/genética , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/patologia , Regulação para Cima
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(6): 513-519, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32696741

RESUMO

Objective To study the protective effect and mechanism of daphnetin (DAP) against myocardial ischemia-reperfusion injury in rats. Methods Seventy-five SD rats were randomly divided into five groups: control group, model group, (30, 60, 90) mg/kg DAP-treated groups. The model of myocardial ischemia in rats was established by isoproterenol (85 mg/kg) through subcutaneous injection for 2 consecutive days. DAP was administered by gavage for 7 consecutive days to observe the protective effect of DAP on the injury of rat myocardium. The electrocardiographic changes of each group of experimental rats were measured with electrocardiographic measuring device. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in the sera were detected with spectrophotometry. The serum levels of creatine kinase isoenzyme, muscle b (CK-MB), lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), and the content of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), IL-6 in the homogenate of myocardial tissue were measured by ELISA. The injury and fibrosis of cardiomyocytes were observed by HE staining and Masson staining, the mRNA levels of JNK and NF-κB were detected by real-time quantitative PCR, and the phosphorylation of JNK and NF-κB were determined by Western blot analysis. Results DAP increased the activities of SOD, CAT, GSH-Px, decreased MDA, inhibited the levels of CK-MB, LDH, CPK, TNF-α and IL-ß in the sera, decreased myocardial fibrosis, depressed the expression and phosphorylation of JNK and NF-κBp65. Conclusion DAP can inhibit the activation of JNK/NF-κB signal pathway and myocardial apoptosis and fibrosis induced by myocardial ischemia-reperfusion.


Assuntos
Isquemia Miocárdica , Animais , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Umbeliferonas
10.
Life Sci ; 257: 118004, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621918

RESUMO

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.


Assuntos
Dexmedetomidina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Apoptose/efeitos dos fármacos , China , Dexmedetomidina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Isquemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Am J Physiol Heart Circ Physiol ; 319(2): H396-H409, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32678707

RESUMO

Myocardial ischemia leads to conduction slowing, cell-to-cell uncoupling, and arrhythmias. We previously demonstrated that varying perfusate sodium (Na+) and calcium (Ca2+) attenuates conduction slowing and arrhythmias during simulated ischemia with continuous perfusion. Cardioprotection was selectively associated with widening of the perinexus, a gap junction adjacent nanodomain important to ephaptic coupling. It is unknown whether perfusate composition affects the perinexus or ischemic conduction during nonsimulated ischemia, when coronary flow is reduced or halted. We hypothesized that altering preischemic perfusate composition could facilitate perinexal expansion and attenuate conduction slowing during global ischemia. To test this hypothesis, ex vivo guinea pig hearts (n = 49) were Langendorff perfused with 145 or 153 mM Na+ and 1.25 or 2.0 mM Ca2+ and optically mapped during 30 min of no-flow ischemia. Altering Na+ and Ca2+ did not substantially affect baseline conduction. Increasing Na+ and decreasing Ca2+ both lowered pacing thresholds, whereas increasing Ca2+ narrowed perinexal width (Wp). A least squares mean estimate revealed that reduced perfusate Na+ and Ca2+ resulted in the most severe conduction slowing during ischemia. Increasing Na+ alone modestly attenuated conduction slowing, yet significantly delayed the median time to conduction block (10 to 16 min). Increasing both Na+ and Ca2+ selectively widened Wp during ischemia (22.7 vs. 15.7 nm) and attenuated conduction slowing to the greatest extent. Neither repolarization nor levels of total or phosphorylated connexin43 correlated with conduction slowing or block. Thus, perfusate-dependent widening of the perinexus preserved ischemic conduction and may be an adaptive response to ischemic stress.NEW & NOTEWORTHY Conduction slowing during acute ischemia creates an arrhythmogenic substrate. We have shown that extracellular ionic concentrations can alter conduction by modulating ephaptic coupling. Here, we demonstrate increased extracellular sodium and calcium significantly attenuate conduction slowing during no-flow ischemia. This effect was associated with selective widening of the perinexus, an intercalated disc nanodomain and putative cardiac ephapse. These findings suggest that acute changes in ephaptic coupling may serve as an adaptive response to ischemic stress.


Assuntos
Bradicardia/prevenção & controle , Cálcio/metabolismo , Bloqueio Cardíaco/prevenção & controle , Sistema de Condução Cardíaco/metabolismo , Frequência Cardíaca , Isquemia Miocárdica/metabolismo , Sódio/metabolismo , Potenciais de Ação , Animais , Bradicardia/etiologia , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Circulação Coronária , Modelos Animais de Doenças , Cobaias , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/metabolismo , Bloqueio Cardíaco/fisiopatologia , Preparação de Coração Isolado , Masculino , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Transdução de Sinais , Fatores de Tempo
12.
Nat Commun ; 11(1): 2843, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487995

RESUMO

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Isquemia Miocárdica/metabolismo , Caracteres Sexuais , Transdução de Sinais , Cardiomiopatia Dilatada/patologia , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Isquemia Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Análise de Componente Principal , Mapas de Interação de Proteínas , Proteoma/metabolismo , Proteômica , Doadores de Tecidos
13.
Cardiovasc Ther ; 2020: 3480276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565909

RESUMO

Wenxin Keli (WXKL) is a traditional Chinese medicine drug approved for the treatment of cardiovascular diseases. This study aimed to identify WXKL-targeting genes involved in antiarrhythmic efficacy of WXKL. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) technology platform was used to screen active compounds of WXKL and WXKL-targeting arrhythmia-related genes. A pig model of myocardial ischemia (MI) was established by balloon-expanding the endothelium of the left coronary artery. Pigs were divided into the model group and WXKL group (n = 6). MI, QT interval, heart rate, and arrhythmia were recorded, and the mRNA expression of target genes in myocardial tissues was detected by PCR. Eleven active ingredients of WXKL and eight WXKL-targeting arrhythmia-related genes were screened. Five pathways were enriched, and an "ingredient-gene-path" network was constructed. WXKL markedly decreased the incidence of arrhythmia in the MI pig model (P < 0.05). The QT interval was significantly shortened, and the heart rate was slowed down in the WXKL group compared with the model group (P < 0.05). In addition, the expression of sodium channel protein type 5 subunit alpha (SCN5A) and beta-2 adrenergic receptor (ADRB2) was downregulated, while muscarinic acetylcholine receptor M2 (CHRM2) was upregulated in the WXKL group (P < 0.05). In conclusion, WXKL may shorten the QT interval and slow down the heart rate by downregulating SCN5A and ADRB2 and upregulating CHRM2 during MI. These findings provide novel insight into molecular mechanisms of WXKL in reducing the incidence of ventricular arrhythmia.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Frequência Cardíaca/genética , Masculino , Medicina Tradicional Chinesa , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Mapas de Interação de Proteínas , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Suínos , Porco Miniatura , Fatores de Tempo
14.
PLoS One ; 15(5): e0231797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365112

RESUMO

The pathological process and mechanism of myocardial ischemia (MI) is very complicated, and remains unclear. An integrated proteomic-metabolomics analysis was applied to comprehensively understand the pathological changes and mechanism of MI. Male Sprague-Dawley rats were randomly divided into a mock surgery (MS) group and an MI group. The MI model was made by ligating the left anterior descending coronary artery, twenty-four hours after which, echocardiography was employed to assess left ventricular (LV) function variables. Blood samples and left ventricular tissues were collected for ELISA, metabolomics and proteomics analysis. The results showed that LV function, including ejection fraction (EF) and fractional shortening (FS), was significantly reduced and the level of cTnT in the serum increased after MI. iTRAQ proteomics showed that a total of 169 proteins were altered including 52 and 117 proteins with increased and decreased expression, respectively, which were mainly involved in the following activities: complement and coagulation cascades, tight junction, regulation of actin cytoskeleton, MAPK signaling pathway, endocytosis, NOD-like receptor signaling pathway, as well as phagosome coupled with vitamin digestion and absorption. Altered metabolomic profiling of this transition was mostly enriched in pathways including ABC transporters, glycerophospholipid metabolism, protein digestion and absorption and aminoacyl-tRNA biosynthesis. The integrated metabolomics and proteomics analysis indicated that myocardial injury after MI is closely related to several metabolic pathways, especially energy metabolism, amino acid metabolism, vascular smooth muscle contraction, gap junction and neuroactive ligand-receptor interaction. These findings may contribute to understanding the mechanism of MI and have implication for new therapeutic targets.


Assuntos
Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Doença Aguda , Animais , Masculino , Metabolômica , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/patologia , Miocárdio/química , Miocárdio/patologia , Proteômica , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
15.
Int Heart J ; 61(3): 585-594, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32418959

RESUMO

Ischemic heart disease (IHD) is one of the world's leading causes of human death. Kaempferol (Kae) was proved to have anti-inflammatory, antioxidant, and anticancer effects. Such properties suggested that it might play protective roles in IHD. In this study, we have attempted to disclose the potential regulating mechanisms of Kae in primary cardiomyocytes and H9c2 cells.Cells were first stimulated by oxygen-glucose deprivation (OGD) and then exposed to Kae. CCK-8 assay and flow cytometry were used to examine cell characteristics. Quantitative reverse-transcription polymerase chain reaction was utilized to test the expression levels of miR-15b and TLR4. Afterward, cell transfection, dual-luciferase activity assay, and western blot were used to explore the potential mechanisms.OGD treatment suppressed cell viability, whereas it enhanced cell apoptosis. Besides, OGD treatment enhanced the expression of apoptosis-associated proteins. Kae exposure, however, attenuated the effects that OGD-induced. Further experiments showed that Kae exposure promoted down-regulation of miR-15b, Bcl-2 and TLR4 were a target of miR-15b. Moreover, Kae enhanced the expression of key factors involved in PI3K/AKT and Wnt/ß-catenin pathways, whereas miR-15b mimic reversed the Kae-triggered effects.This investigation revealed that Kae diminished OGD-triggered cell damage through down-regulating miR-15b expression via activating PI3K/AKT and Wnt3a/ß-catenin pathways.


Assuntos
Quempferóis/uso terapêutico , MicroRNAs/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Quempferóis/farmacologia , Isquemia Miocárdica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Wistar , Via de Sinalização Wnt , beta Catenina/metabolismo
16.
J Pharmacol Sci ; 143(3): 156-164, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32278466

RESUMO

Safranal (SFR) is the major constituent of saffron. The purpose of this study was to observe the effect of SFR on myocardial ischemia induced by isoprenaline (ISO) and to explore its possible mechanism. The myocardial ischemia rat model was established by subcutaneous injection of ISO (85 mg/kg/d) on the 8th and 9th day of the experiment. Serum creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured, as were changes in calcium concentration, reactive oxygen species (ROS) and cardiac morphology of the myocardial tissue. The effects of SFR on cell contraction, Ca2+ transient and L-type Ca2+ current (ICa-L) in isolated rat myocardial cells were measured using the Ion Optix detection system and the whole-cell patch-clamp technique. SFR can decrease the activity of serum CK, LDH and MDA, and increase the activity of serum SOD, reduce intracellular calcium concentration and the manufacture of ROS. In addition, SFR can improve changes in heart morphology. SFR can significantly inhibit contraction, Ca2+ transients and ICa-L in isolated ventricular myocytes. SFR has a cardioprotective role in ISO-induced MI rats, and the underling mechanism is related to the inhibition of oxidative stress, myocardial contractility, ICa-L and the regulation of Ca2+ homeostasis.


Assuntos
Cálcio/metabolismo , Crocus/química , Cicloexenos/farmacologia , Cicloexenos/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Terpenos/farmacologia , Terpenos/uso terapêutico , Animais , Cardiotônicos , Células Cultivadas , Cicloexenos/isolamento & purificação , Modelos Animais de Doenças , Isoproterenol/efeitos adversos , Masculino , Malondialdeído/metabolismo , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/induzido quimicamente , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Terpenos/isolamento & purificação
18.
Am J Cardiol ; 125(8): 1194-1201, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32106929

RESUMO

The role of NT-proBNP and hs-cTnT levels in predicting heart failure (HF) and cardiovascular disease (CVD) events in persons with prediabetes (pre-DM) and diabetes mellitus (DM) is not well-established. We examined the individual and combined relations of N-terminal natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) levels among asymptomatic adults with pre-DM and DM with the development of incident HF and CVD events. 5,584 participants with biomarker measures aged 45 to 84 years were included from the Multi-Ethnic Study of Atherosclerosis, of which 4,090 were normoglycemic, 799 had pre-DM, and 695 had DM at baseline and were followed for 12.4 ± 3.8 years. In those with DM, HF incidence rates per 1,000 person-years ranged from 3.2 to 39.4 across quartiles of NT-proBNP and 0.6 to 18.2 for hs-cTnT, respectively. Corresponding values for CVD incidence per 1,000 person-years ranged from 13.7 to 39.4 for NT-proBNP and 13.2 to 35.4 for hs-cTnT. Multivariate adjusted HRs were highest when both NT-proBNP and hs-cTnT were above versus below the median in those with pre-DM/DM (16.7 for incident HF and 2.1 for CVD events, both p <0.01). In conclusion, the combination of both biomarkers to traditional risk factors in participants who were normoglycemic or with pre-DM or DM improved risk prediction for both incident HF and total CVD events in an ethnically diverse population.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insuficiência Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Estado Pré-Diabético/metabolismo , Acidente Vascular Cerebral/metabolismo , Troponina T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/epidemiologia , Angina Pectoris/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doença das Coronárias/metabolismo , Doença das Coronárias/mortalidade , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/mortalidade , Medição de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Estados Unidos/epidemiologia
19.
Mediators Inflamm ; 2020: 6079713, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104149

RESUMO

Background: Heart failure with reduced ejection fraction (HFrEF) constitutes a global health issue. While proinflammatory cytokines proved to have a pivotal role in the development and progression of HFrEF, less attention has been paid to the cellular immunity. Regulatory T lymphocytes (Tregs) seem to have an important role in the induction and maintenance of immune homeostasis. Therefore, we aimed to investigate the impact of Tregs on the outcome in HFrEF. Methods: We prospectively enrolled 112 patients with HFrEF and performed flow cytometry for cell phenotyping. Individuals were stratified in ischemic (iHFrEF, n = 57) and nonischemic etiology (niHFrEF, n = 57) and nonischemic etiology (niHFrEF. Results: Comparing patients with iHFrEF to niHFrEF, we found a significantly lower fraction of Tregs within lymphocytes in the ischemic subgroup (0.42% vs. 0.56%; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92. Conclusion: Our results indicate a potential influence of Tregs in the pathogenesis and progression of iHFrEF, fostering the implication of cellular immunity in iHFrEF pathophysiology and proving Tregs as a predictor for long-term survival among iHFrEF patients. A preview of this study has been presented at a meeting of the European Society of Cardiology earlier this year.


Assuntos
Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/mortalidade , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/mortalidade , Linfócitos T Reguladores/metabolismo , Linfócitos T/metabolismo , Idoso , Feminino , Citometria de Fluxo , Insuficiência Cardíaca/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Prognóstico , Estudos Prospectivos , Fatores de Risco , Volume Sistólico/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
20.
Am J Cardiol ; 125(8): 1137-1141, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32093953

RESUMO

We examined the baseline characteristics, rates of implantable cardioverter defibrillator implantation, and long-term all-cause mortality for survivors of in-hospital (IHSCA) versus out-of-hospital (OHSCA) sudden cardiac arrest (SCA). A total of 1,433 SCA survivors (807 IHSCA and 626 OHSCA) from 2002 to 2012 were followed through February 2017. Baseline characteristics and potential triggers of SCA, including significant electrolyte and metabolic abnormalities and acute myocardial infarction and ischemia, were collected. Adjusted survival analyses were performed using a multivariate Cox model. The presence of SCA triggers was similar between IHSCA and OHSCA patients (39% vs 35%, p = 0.3), but OHSCA was more likely associated with cardiac ischemia and drug abuse, whereas IHSCA was more associated with new antiarrhythmic drugs (p <0.05). OHSCA survivors were more likely to receive an implantable cardioverter defibrillator (38% vs 18%, p <0.001). Over a median follow-up of 3.6 years, 674 (47%) patients died. After adjusting for unbalanced baseline characteristics, survival was similar between IHSCA and OHSCA survivors (hazard ratio 1.1, 95% confidence interval 0.9 to 1.3, p = 0.4). In conclusion, survivors of IHSCA and OHSCA differed in baseline characteristic, potential SCA triggers, and treatment interventions but their adjusted survival was comparable.


Assuntos
Mortalidade , Isquemia Miocárdica/fisiopatologia , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/fisiopatologia , Desequilíbrio Hidroeletrolítico/fisiopatologia , Fatores Etários , Idoso , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/epidemiologia , Causas de Morte , Comorbidade , Desfibriladores Implantáveis , Eletrocardiografia , Feminino , Parada Cardíaca/epidemiologia , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Parada Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/complicações , Isquemia Miocárdica/metabolismo , Parada Cardíaca Extra-Hospitalar/epidemiologia , Parada Cardíaca Extra-Hospitalar/etiologia , Parada Cardíaca Extra-Hospitalar/terapia , Prognóstico , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Volume Sistólico , Transtornos Relacionados ao Uso de Substâncias/complicações , Sobreviventes , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/etiologia , Desequilíbrio Hidroeletrolítico/complicações , Desequilíbrio Hidroeletrolítico/metabolismo
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