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Vitamin K2 (MK-7) has been shown to cause significant changes in different physiological processes and diseases, but its role in acute lung injury (ALI) is unclear. Therefore, in this study, we aimed to evaluate the protective effects of VK2 against LPS-induced ALI in mice. The male C57BL/6J mice were randomly divided into six groups (n = 7): the control group, LPS group, negative control group (LPS + Oil), positive control group (LPS + DEX), LPS + VK2 (L) group (VK2, 1.5 mg/kg), and LPS + VK2 (H) group (VK2, 15 mg/kg). Hematoxylin-eosin (HE) staining of lung tissue was performed. Antioxidant superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities, and the Ca2+ level in the lung tissue were measured. The effects of VK2 on inflammation, apoptosis, tight junction (TJ) injury, mitochondrial dysfunction, and autophagy were quantitatively assessed using Western blot analysis. Compared with the LPS group, VK2 improved histopathological changes; alleviated inflammation, apoptosis, and TJ injury; increased antioxidant enzyme activity; reduced Ca2+ overload; regulated mitochondrial function; and inhibited lung autophagy. These results indicate that VK2 could improve tight junction protein loss, inflammation, and cell apoptosis in LPS-induced ALI by inhibiting the mitochondrial dysfunction and excessive autophagy, indicating that VK2 plays a beneficial role in ALI and might be a potential therapeutic strategy.
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Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and there is a huge unmet need to find safer and more effective drugs. Vitamin K has been found to regulate lipid metabolism in the liver. However, the effects of vitamin K2 on NAFLD is unclear. This study aims to evaluate the preventive and therapeutic effects of vitamin K2 in the process of fatty liver formation and to explore molecular mechanisms the associated with lipid metabolism. A non-alcoholic fatty liver model was established by high-fat diet administration for three months. Vitamin K2 significantly reduced the body weight, abdominal circumference and body fat percentage of NAFLD mice. Vitamin K2 also showed histological benefits in reducing hepatic steatosis. NAFLD mice induced by high-fat diet showed increased HMGR while vitamin K2 intervention could reverse the pathological lterations. Adiponectin (APN) is an endogenous bioactive polypeptide or protein secreted by adipocytes. We detected APN, SOD, AlaDH and other indicators that may affect the state of high-fat diet mice, but the experimental results showed that the above indicators did not change significantly. It is worth noting that the effect of vitamin K2 supplementation on the lipid-lowering effect of uc OC in vivo needs to be further explored. This study first reported the protective effect of vitamin K2 on high-fat diet-induced NAFLD in mice. The protective effect of vitamin K2 may be related to the improvement of lipid metabolism disorder in NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/patologia , Vitamina K 2/metabolismo , Dieta Hiperlipídica , Fígado/metabolismo , Metabolismo dos Lipídeos , Adiponectina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Vitamin K (VK) comprises a group of substances with chlorophyll quinone bioactivity and exists in nature in the form of VK1 and VK2. As its initial recognition originated from the ability to promote blood coagulation, it is known as the coagulation vitamin. However, based on extensive research, VK has shown potential for the prevention and treatment of various diseases. Studies demonstrating the beneficial effects of VK on immunity, antioxidant capacity, intestinal microbiota regulation, epithelial development, and bone protection have drawn growing interest in recent years. This review article focuses on the mechanism of action of VK and its potential preventive and therapeutic effects on infections (eg, asthma, COVID-19), inflammation (eg, in type 2 diabetes mellitus, Alzheimer's disease, Parkinson's disease, cancer, aging, atherosclerosis) and autoimmune disorders (eg, inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis). In addition, VK-dependent proteins (VKDPs) are another crucial mechanism by which VK exerts anti-inflammatory and immunomodulatory effects. This review explores the potential role of VK in preventing aging, combating neurological abnormalities, and treating diseases such as cancer and diabetes. Although current research appoints VK as a therapeutic tool for practical clinical applications in infections, inflammation, and autoimmune diseases, future research is necessary to elucidate the mechanism of action in more detail and overcome current limitations.
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Acute lung injury (ALI) is a life-threatening disease that has received considerable critical attention in the field of intensive care. This study aimed to explore the role and mechanism of vitamin K2 (VK2) in ALI. Intraperitoneal injection of 7 mg/kg LPS was used to induce ALI in mice, and VK2 injection was intragastrically administered with the dose of 0.2 and 15 mg/kg. We found that VK2 improved the pulmonary pathology, reduced myeloperoxidase (MPO) activity and levels of TNF-α and IL-6, and boosted the level of IL-10 of mice with ALI. Moreover, VK2 played a significant part in apoptosis by downregulating and upregulating Caspase-3 and Bcl-2 expressions, respectively. As for further mechanism exploration, we found that VK2 inhibited P38 MAPK signaling. Our results also showed that VK2 inhibited ferroptosis, which manifested by reducing malondialdehyde (MDA) and iron levels, increasing glutathione (GSH) level, and upregulated and downregulated glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HO-1) expressions, respectively. In addition, VK2 also inhibited elastin degradation by reducing levels of uncarboxylated matrix Gla protein (uc-MGP) and desmosine (DES). Overall, VK2 robustly alleviated ALI by inhibiting LPS-induced inflammation, apoptosis, ferroptosis, and elastin degradation, making it a potential novel therapeutic candidate for ALI.
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Lesão Pulmonar Aguda , Ferroptose , Camundongos , Animais , Lipopolissacarídeos/efeitos adversos , Vitamina K 2/efeitos adversos , Elastina , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Apoptose , Pulmão/patologiaRESUMO
Mechanical trauma can (MT) cause secondary injury, such as cardiomyocyte apoptosis and cardiac dysfunction has been reported. However, the effects of mechanical trauma on gastrointestinal tract is unclear. This study aims to observe the main location and time of gastrointestinal tract injury caused by non-directional trauma and explain the reason of the increase of LPS in blood caused by mechanical injury. Morphological changes in the stomach, ileum and cecum at different time points after MT were observed in this experiment. The results reveal that the injury to the cecal mucosa in the rats was more obvious than that in the ileum and the stomach. The cecal epithelial cell junction was significantly widened at 20 min after MT, and the plasma LPS and D-lactic acid concentrations increased significantly at the same time point. In addition, some bacterial structures in the widened intercellular space and near the capillary wall of the cecal mucosa were detected at 12 h after MT. This finding suggests that the main reason for the increase in LPS in plasma after MT is cecal mucosal injury. This study is important for the early intervention of the gastrointestinal tract to prevent secondary injury after MT.
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Vitamin Kdependent proteins (VKDPs) are a group of proteins that need vitamin K to conduct carboxylation. Thus far, scholars have identified a total of 17 VKDPs in the human body. In this review, we summarize three important emerging VKDPs: Growth arrestspecific protein 6 (Gas 6), Glarich protein (GRP) and periostin in terms of their functions in physiological and pathological conditions. As examples, carboxylated Gas 6 and GRP effectively protect blood vessels from calcification, Gas 6 protects from acute kidney injury and is involved in chronic kidney disease, GRP contributes to bone homeostasis and delays the progression of osteoarthritis, and periostin is involved in all phases of fracture healing and assists myocardial regeneration in the early stages of myocardial infarction. However, periostin participates in the progression of cardiac fibrosis, idiopathic pulmonary fibrosis and airway remodeling of asthma. In addition, we discuss the relationship between vitamin K, VKDPs and cancer, and particularly the carboxylation state of VKDPs in cancer.
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Moléculas de Adesão Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Infarto do Miocárdio/metabolismo , Osteoartrite/metabolismo , Insuficiência Renal Crônica/metabolismo , Vitamina K/metabolismo , Animais , Humanos , Infarto do Miocárdio/patologia , Osteoartrite/patologia , Insuficiência Renal Crônica/patologiaRESUMO
In postmenopausal women and elderly men, bone density decreases with age and vascular calcification is aggravated. This condition is closely associated with vitamin K2 deficiency. A total of 17 different vitamin Kdependent proteins have been identified to date. Vitamin Kdependent proteins are located within the bone, heart and blood vessels. For instance, carboxylated osteocalcin is beneficial for bone and aids the deposition of calcium into the bone matrix. Carboxylated matrix Gla protein effectively protects blood vessels and may prevent calcification within the vascular wall. Furthermore, carboxylated Glarich protein has been reported to act as an inhibitor in the calcification of the cardiovascular system, while growth arrestspecific protein6 protects endothelial cells and vascular smooth muscle cells, resists apoptosis and inhibits the calcification of blood vessels by inhibiting the apoptosis of vascular smooth muscle cells. In addition, periostin may promote the differentiation, aggregation, adhesion and proliferation of osteoblasts. Periostin also occurs in the heart and may be associated with the reconstruction of heart function. These vitamin Kdependent proteins may exert their functions following γcarboxylation with vitamin K, and different vitamin Kdependent proteins may exhibit synergistic effects or antagonistic effects on each other. In the cardiovascular system with vitamin K antagonist supplement or vitamin K deficiency, calcification occurs in the endothelium of blood vessels and vascular smooth muscle cells are transformed into osteoblastlike cells, a phenomenon that resembles bone growth. Both the bone and cardiovascular system are closely associated during embryonic development. Thus, the present study hypothesized that embryonic developmental position and tissue calcification may have a certain association for the bone and the cardiovascular system. This review describes and briefly discusses several important vitamin Kdependent proteins that serve an important role in bone and the cardiovascular system. The results of the review suggest that the vascular calcification and osteogenic differentiation of vascular smooth muscle cells may be associated with the location of the bone and cardiovascular system during embryonic development.
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Envelhecimento/metabolismo , Densidade Óssea , Doenças Cardiovasculares/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Vitamina K/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/patologiaRESUMO
Despite the availability of multiple therapeutic methods for patients with cancer, the long-term prognosis is not satisfactory in a number of different cancer types. Vitamin K2 (VK2), which exerts anticancer effects on a number of cancer cell lines, is considered to be a prospective novel agent for the treatment of cancer. The present review aims to summarize the results of studies in which VK2 was administered either to patients with cancer or animals inoculated with cancerous cells, particularly investigating the inhibitory effects of VK2 on cancerous cells, primarily involving cell-cycle arrest, cell differentiation, apoptosis, autophagy and invasion. The present review summarizes evidence stating that treatment with VK2 could positively inhibit the growth of cancer cells, making it a potentially useful approach for the prevention and clinical treatment of cancer. Additionally, the combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects. Therefore, more attention should be paid to the effects of micronutrients on tumors.
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Type 2 diabetes mellitus (T2DM) continue to be a major public health problem around the world that frequently presents with microvascular and macrovascular complications. Individuals with T2DM are not only suffering from significant emotional and physical misery, but also at increased risk of dying from severe complications. In recent years, evidence from prospective observational studies and clinical trials has shown T2DM risk reduction with vitamin K2 supplementation. We thus did an overview of currently available studies to assess the effect of vitamin K2 supplementation on insulin sensitivity, glycaemic control and reviewed the underlying mechanisms. We proposed that vitamin K2 improved insulin sensitivity through involvement of vitamin K-dependent-protein osteocalcin, anti-inflammatory properties, and lipid-lowering effects. Vitamin K2 had a better effect than vitamin K1 on T2DM. The interpretation of this review will increase comprehension of the development of a therapeutic strategy to prevent and treat T2DM.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Vitamina K 2/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vitamina K 2/farmacologia , Adulto JovemRESUMO
Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca2+ overload in cardiomyocytes.
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Curcumina/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Fenômenos Mecânicos , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Hemodinâmica/efeitos dos fármacos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangueRESUMO
Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.
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Transplante de Coração/métodos , Canais de Potencial de Receptor Transitório/fisiologia , Aloenxertos/fisiologia , Doença da Artéria Coronariana/terapia , Cardiopatias/fisiopatologia , Humanos , Fatores de Risco , Transplante Homólogo/métodosRESUMO
Multiple organ dysfunctional syndrome secondary to mechanical trauma (MT) has attracted considerable research attention. The heart is one of the most important organs of the body, and secondary cardiac insufficiency caused by MT seriously affects the quality of life. This study aims to investigate whether proanthocyanidin can alleviate myocardial injury and improve heart function in the process of MT leading to secondary cardiac insufficiency. Noble-Collip drum wasused to prepare MT model in rats. And myocardial apoptosis index was calculated after TUNEL staining. Ventricular intubation was employed to detect heart function. Changes in myocardial ultrastructure were observed using an electron microscope. ELISA was used to detect the content of TNF-α and reactive oxygen species generated from monocytes and cardiomyocytes. The changes in Ca2+ concentration in cardiomyocyte were observed by confocal microscope. Compared with trauma group, the administration group had a decreased apoptosis index of cardiomyocytes, and increased ±dp/dtmax. Meanwhile, proanthocyanidin can inhibit monocytes' TNF-α production, and reduce plasma TNF-α concentration. Moreover, proanthocyanidin can attenuate the excessive oxidative stress reaction of cardiomyocyte, and inhibit calcium overload in cardiomyocytes. In conclusion, proanthocyanidin can effectively ease myocardial damage and improve cardiac function, through anti-inflammatory and antioxidant effects in secondary cardiac insufficiency caused by MT.
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Antioxidantes/administração & dosagem , Traumatismos Cardíacos/tratamento farmacológico , Proantocianidinas/administração & dosagem , Ferimentos e Lesões/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Traumatismos Cardíacos/genética , Traumatismos Cardíacos/fisiopatologia , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética , Ferimentos e Lesões/fisiopatologiaRESUMO
Asthma is characterized by airway inflammation, airway obstruction, and airway hyperresponsiveness (AHR), and it affects 300 million people worldwide. However, our current understanding of the molecular mechanisms that underlie asthma remains limited. Recent studies have suggested that transient receptor potential ankyrin 1 (TRPA1), one of the transient receptor potential cation channels, may be involved in airway inflammation in asthma. The present review discusses the relationship between TRPA1 and neurogenic inflammation in asthma, hoping to enhance our understanding of the mechanisms of airway inflammation in asthma.
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Asma/metabolismo , Asma/patologia , Canais de Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Inflamação Neurogênica/metabolismo , Inflamação Neurogênica/patologia , Canais de Potencial de Receptor Transitório/metabolismo , Humanos , Fibras Nervosas Amielínicas/metabolismo , Fibras Nervosas Amielínicas/patologia , Sistema Respiratório , Canal de Cátion TRPA1RESUMO
Quercetin is an important dietary flavonoid present in fruits and vegetables and has attracted attention because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play important roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This study investigates the protective effect of quercetin on trauma-induced secondary cardiac injury and the mechanisms involved. Widely accepted nonlethal mechanical trauma models were established. In vivo, cardiomyocyte apoptosis and cardiac dysfunction in rats were assessed using TUNEL staining and a biological mechanic experiment system. In vitro, cell viability, tumour necrosis factor-α (TNF-α), reactive oxygen species (ROS) and [Ca(2+)]i of H9c2 cells were detected using an MTT assay, ELISA, and 2',7'-dichlorofluorescin diacetate and fluo-4 acetoxymethyl ester assays respectively. Quercetin pretreatment (20 mg/kg i.p.; 0.5 h before trauma) significantly improved posttraumatic cardiomyocyte apoptosis and cardiac dysfunction. Pretreatment with quercetin (20 µM; 24 h before trauma plasma addition) significantly attenuated trauma-induced viability decreases, TNF-α increases, ROS overproduction and [Ca(2+)]i overload in H9c2 cells. In conclusion, quercetin may reverse posttraumatic cardiac dysfunction by reducing cardiomyocyte apoptosis through the suppression of TNF-α increases, ROS overproduction and Ca(2+) overload in cardiomyocytes, representing a potential preventive approach for the treatment of secondary cardiac injury after mechanical trauma.
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Antioxidantes/administração & dosagem , Traumatismos Cardíacos/fisiopatologia , Miócitos Cardíacos/citologia , Quercetina/administração & dosagem , Animais , Antioxidantes/farmacologia , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CONTEXT: Recent ecological evidence has showed a lag-correlation between the prevalence of diabetes and consumption of niacin (nicotinamide and nicotinic acid) in the US. Nicotinamide has been demonstrated to induce insulin resistance due to excess reactive oxygen species and methyl depletion, whereas the effect of nicotinic acid is poorly understood. OBJECTIVE: To examine the mechanism of the effect of nicotinic acid on glucose metabolism. MATERIALS AND METHODS: Rats were injected with different cumulative doses of nicotinic acid (0.5, 2, 4 g/kg) and nicotinamide (2 g/kg). A glucose tolerance test was given 2 h after the final injection. The role of methyl consumption and reactive oxygen species generation were evaluated by measuring N(1)-methylnicotinamide and hydrogen peroxide. RESULTS: Cumulative doses of nicotinic acid produced a dose-dependent increase in the plasma levels of N(1)-methylnicotinamide and hydrogen peroxide, which was associated with a decrease in liver and skeletal muscle glycogen levels. At the same dosage (2 g/kg), in comparison with nicotinamide, nicotinic acid was weaker in raising plasma N(1)-methylnicotinamide levels (0.7 ± 0.11 µg/mL vs. 4.69 ± 0.24 µg/mL, P < 0.001), but stronger in increasing plasma hydrogen peroxide levels (1.88 ± 0.07 µmol/L vs. 1.55 ± 0.05 µmol/L, P < 0.001). Moreover, nicotinamide, unlike nicotinic acid, did not reduce liver glycogen levels. DISCUSSION AND CONCLUSION: This study suggested that excessive nicotinic acid, like nicotinamide, might induce methyl consumption, oxidative stress and insulin resistance. Long-term consumption high niacin may increase the risk of type 2 diabetes.
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Glucose/metabolismo , Peróxido de Hidrogênio/metabolismo , Niacina/farmacologia , Niacinamida/farmacologia , Animais , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Niacina/administração & dosagem , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
The Naâº/Ca²âº exchanger (NCX) is an important electrogenic transporter in maintaining Na⺠and Ca²âº homeostasis in a variety of mammalian organs, and is involved in the physiological and pathophysiological regulation of Ca²âº concentration in the myocardium. It can affect cardial structure, electrophysiology and contractile properties. The role of the NCX in heart cells following ischemia/reperfusion (IR) has been investigated using a number of in vitro and in vivo models. During ischemia, ionic disturbances favor Ca²âº-influx mode activity as excess Na⺠is extruded in exchange for Ca²âº, giving rise to increased intracellular Ca²âº levels (Cai). This rise in Cai contributes to reversible cellular dysfunction upon reperfusion, such as myocardial necrosis, arrhythmia, systolic dysfunction and heart failure. We have reviewed the major in vivo and in vitro cardiac IR-related NCX studies in an attempt to clarify the functions of NCX in IR and conclude that recent studies suggest blockage of NCX has potential therapeutic applications. Although the use of different IR models, application of NCX stimulators and inhibitors, and development of NCX transgenic animals do help elucidate the role of this ion exchanger in heart cells, related mechanisms are not completely understood and clinically effective specific NCX inhibitors need further research.
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Traumatismo por Reperfusão Miocárdica/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , NecroseAssuntos
Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases , Canais de Cátion TRPM/efeitos dos fármacos , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imunidade/efeitos dos fármacos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Canais de Cátion TRPM/metabolismoRESUMO
Whole body non-penetrating trauma causes myocardial infarction in humans and mechanical trauma (MT) results in cardiac dysfunction in animals. Our recent study demonstrated that incubation of cardiomyocytes with plasma isolated from MT animals causes significant cardiomyocyte apoptosis that can be blocked by neutralization of TNFalpha. The present study attempted to obtain direct in vivo evidence to support that overproduction of TNFalpha plays a causative role in trauma-induced cardiomyocyte apoptosis. Non-lethal MT caused significant TNFalpha overproduction (2.4-fold at 1.5 h after MT) and increased cardiomyocyte apoptosis (starting 3 h and peaking 12 h after MT). Pharmacological inhibition of TNFalpha with etanercept or TNFalpha gene deletion reduced post-trauma myocyte apoptosis (P<0.01). Expression of iNOS and NADPH oxidase, overproduction of NO and O2-, and excessive protein nitration in the MT heart were all significantly reduced in etanercept-treated or TNFalpha-/- mice, suggesting that oxidative/nitrative stress may contribute to TNFalpha-initiated myocyte apoptosis in MT hearts. Additional experiments demonstrated that inhibiting iNOS (1400W) or NADPH oxidase (apocynin), or scavenging peroxynitrite (FP15) significantly reduced myocyte apoptosis in MT animals (P<0.01). Collectively, these data demonstrated that non-lethal mechanical trauma caused significant TNFalpha production that in turn stimulated myocardial apoptosis via oxidative/nitrative stress.
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Apoptose/fisiologia , Miócitos Cardíacos/fisiologia , Nitritos/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo , Ferimentos e Lesões , Acetofenonas/metabolismo , Animais , Inibidores Enzimáticos/metabolismo , Humanos , Masculino , Metaloporfirinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/citologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Ácido Peroxinitroso/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética , Ferimentos e Lesões/patologia , Ferimentos e Lesões/fisiopatologiaRESUMO
Mechanical traumatic injury causes cardiomyocyte apoptosis and cardiac dysfunction. However, the signaling mechanisms leading to posttraumatic cardiomyocyte apoptosis remains unclear. The present study attempted to identify the molecular mechanisms responsible for cardiomyocyte apoptosis induced by trauma. Normal cardiomyocytes (NC) or traumatic cardiomyocytes (TC; isolated immediately after trauma) were cultured with normal plasma (NP) or traumatic plasma (TP; isolated 1.5 h after trauma) for 12 h, and apoptosis was determined by caspase-3 activation. Exposure of TC to NP failed to induce significant cardiomyocyte apoptosis. In contrast, exposure of NC to TP resulted in a greater than twofold increase in caspase-3 activation (P < 0.01). Incubation of cardiomyocytes with cytomix (a mixture of TNF-alpha, IL-1beta, and IFN-gamma) or TNF-alpha alone, but not with IL-1beta or IFN-gamma alone, caused significant caspase-3 activation (P < 0.01). TP-induced caspase-3 activation was virtually abolished by an anti-TNF-alpha antibody, and TP isolated from TNF-alpha(-/-) mice failed to induce caspase-3 activation. Moreover, incubation of cardiomyocytes with TP upregulated inducible nitric oxide (NO) synthase (iNOS)/NADPH oxidase expression, increased NO/superoxide production, and increased cardiomyocyte protein nitration (measured by nitrotyrosine content). These oxidative/nitrative stresses and the resultant cardiomyocyte caspase-3 activation can be blocked by neutralization of TNF-alpha (anti-TNF-alpha antibody), inhibition of iNOS (1400W), or NADPH oxidase (apocynin) and scavenging of peroxynitrite (FP15) (P < 0.01). Taken together, our study demonstrated that there exists a TNF-alpha-initiated, cardiomyocyte iNOS/NADPH oxidase-dependent, peroxynitrite-mediated signaling pathway that contributes to posttraumatic myocardial apoptosis. Therapeutic interventions that block this signaling cascade may attenuate posttraumatic cardiac injury and reduce the incidence of secondary organ dysfunction after trauma.