RESUMEN
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, having become a global public health problem, so the pathophysiological mechanisms and therapeutic strategies of CVDs need further study. Legumain is a powerful enzyme that is widely distributed in mammals and plays an important role in a variety of biological processes. Recent research suggests that legumain is associated with the occurrence and progression of CVDs. In this review, we provide a comprehensive overview of legumain in the pathogenesis of CVDs. The role of legumain in CVDs, such as carotid atherosclerosis, pulmonary hypertension, coronary artery disease, peripheral arterial disease, aortic aneurysms and dissection, is discussed. The potential applications of legumain as a biomarker of these diseases are also explored. By understanding the role of legumain in the pathogenesis of CVDs, we aim to support new therapeutic strategies to prevent or treat these diseases.
Asunto(s)
Enfermedades Cardiovasculares , Cisteína Endopeptidasas , Humanos , Cisteína Endopeptidasas/metabolismo , Enfermedades Cardiovasculares/enzimología , Animales , Biomarcadores/metabolismoRESUMEN
BACKGROUND: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. METHODS: We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. RESULTS: Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL (myeloproliferative leukemia virus oncogene) suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. CONCLUSIONS: JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.
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Enfermedades Cardiovasculares , Células Endoteliales , Células Madre Pluripotentes Inducidas , Janus Quinasa 2 , Mutación , Trastornos Mieloproliferativos , Receptores de Trombopoyetina , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Receptores de Trombopoyetina/genética , Animales , Humanos , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/metabolismo , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/etiología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/enzimología , Ratones Transgénicos , Transducción de Señal , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , RatonesRESUMEN
Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.
Asunto(s)
Enfermedades Cardiovasculares , Proteínas Serina-Treonina Quinasas , Humanos , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Fosforilación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.
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Quinasa de Cadena Ligera de Miosina , Transducción de Señal , Humanos , Quinasa de Cadena Ligera de Miosina/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/enzimología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.
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Enfermedades Cardiovasculares , Mitocondrias Cardíacas , Miocitos Cardíacos , Sirtuinas , Sirtuinas/metabolismo , Humanos , Mitocondrias Cardíacas/patología , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/enzimología , Mitocondrias Cardíacas/efectos de los fármacos , Animales , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/patología , Transducción de Señal , Metabolismo Energético/efectos de los fármacosRESUMEN
Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the formation of uric acid (UA) and is involved in the generation of reactive oxygen species (ROS). Overproduction of ROS has been linked to the pathogenesis of hypertension, atherosclerosis, and cardiovascular disease, with multiple studies over the last 30 years demonstrating that XOR inhibition is beneficial. The involvement of XOR and its constituents in the advancement of chronic inflammation and ROS, which are responsible for endothelial dysfunction, is the focus of this evidence-based review. An overabundance of XOR products and ROS appears to drive the inflammatory response, resulting in significant endothelium damage. It has also been demonstrated that XOR activity and ED are connected. Diabetes, hypertension, and cardiovascular disease are all associated with endothelial dysfunction. ROS mainly modifies the activity of vascular cells and can be important in normal vascular physiology as well as the development of vascular disease. Suppressing XOR activity appears to decrease endothelial dysfunction, probably because it lessens the generation of reactive oxygen species and the oxidative stress brought on by XOR. Although there has long been a link between higher vascular XOR activity and worse clinical outcomes, new research suggests a different picture in which positive results are mediated by XOR enzymatic activity. Here in this study, we aimed to review the association between XOR and vascular endothelial dysfunction. The prevention and treatment approaches against vascular endothelial dysfunction in atherosclerotic disease.
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Endotelio Vascular , Estrés Oxidativo , Especies Reactivas de Oxígeno , Xantina Deshidrogenasa , Humanos , Xantina Deshidrogenasa/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , Endotelio Vascular/enzimología , Especies Reactivas de Oxígeno/metabolismo , Animales , Hipertensión/fisiopatología , Hipertensión/enzimología , Hipertensión/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/metabolismo , Ácido Úrico/metabolismo , Ácido Úrico/sangre , Inhibidores Enzimáticos/farmacologíaRESUMEN
cGMP-dependent protein kinase (PKG) represents a compelling drug target for treatment of cardiovascular diseases. PKG1 is the major effector of beneficial cGMP signaling which is involved in smooth muscle relaxation and vascular tone, inhibition of platelet aggregation and signaling that leads to cardioprotection. In this study, a novel piperidine series of activators previously identified from an ultrahigh-throughput screen were validated to directly bind partially activated PKG1α and subsequently enhance its kinase activity in a concentration-dependent manner. Compounds from initial optimization efforts showed an ability to activate PKG1α independent of the endogenous activator, cGMP. We demonstrate these small molecule activators mimic the effect of cGMP on the kinetic parameters of PKG1α by positively modulating the KM of the peptide substrate and negatively modulating the apparent KM for ATP with increase in catalytic efficiency, kcat. In addition, these compounds also allosterically modulate the binding affinity of cGMP for PKG1α by increasing the affinity of cGMP for the high-affinity binding site (CNB-A) and decreasing the affinity of cGMP for the low-affinity binding site (CNB-B). We show the mode of action of these activators involves binding to an allosteric site within the regulatory domain, near the CNB-B binding site. To the best of our knowledge, these are the first reported non-cGMP mimetic small molecules shown to directly activate PKG1α. Insights into the mechanism of action of these compounds will enable future development of cardioprotective compounds that function through novel modes of action for the treatment of cardiovascular diseases.
Asunto(s)
Enfermedades Cardiovasculares , Proteína Quinasa Dependiente de GMP Cíclico Tipo I , GMP Cíclico , Piperidinas , Adenosina Trifosfato/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/enzimología , GMP Cíclico/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Humanos , Piperidinas/farmacología , Piperidinas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Background and Objective. 5-Fluorouracil is one of the most common chemotherapeutic agents used in the treatment of solid tumors. 5-Fluorouracil-associated cardiotoxicity is the second cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. Colchicine is a strong anti-inflammatory drug used to prevent and treat acute gout and treat familial Mediterranean fever. And also, its protective effects on cardiovascular disease have been reported in various studies. The current study is aimed at appraising the effect of colchicine on 5-fluorouracil-induced cardiotoxicity in rats. Methods. Twenty male Wistar rats were divided into four groups as follows: control, 5-fluorouracil, colchicine (5 mg/kg), and 5-fluorouracil+5 mg/kg colchicine. Cardiotoxicity was induced with an intraperitoneal injection of a single dose of 5-fluorouracil (100 mg/kg). The control group received normal saline, and the treatment groups received colchicine with an intraperitoneal injection for 14 days. Findings. 5-Fluorouracil resulted in significant cardiotoxicity represented by an increase in cardiac enzymes, malondialdehyde levels, cyclooxygenase-2 and tumor necrosis factor-alpha expression, cardiac enzymes, and histopathological degenerations. 5-Fluorouracil treatment also decreased body weight, total antioxidant capacity and catalase values, blood cells, and hemoglobin levels. In addition, 5-fluorouracil disrupted electrocardiographic parameters, including increased elevation in the ST segment and increased QRS duration. Treatment with colchicine reduced oxidative stress, cardiac enzymes, histopathological degenerations, and cyclooxygenase-2 expression in cardiac tissue, improved electrocardiographic disorders, and enhanced the number of blood cells and total antioxidant capacity levels. Moreover, body weight loss was hampered after treatment with colchicine. Our results demonstrated that treatment with colchicine significantly improved cardiotoxicity induced by 5-fluorouracil in rats.
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Antimetabolitos Antineoplásicos/efectos adversos , Antioxidantes/administración & dosificación , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/tratamiento farmacológico , Colchicina/administración & dosificación , Colchicum/química , Fluorouracilo/efectos adversos , Fitoquímicos/administración & dosificación , Fitoterapia/métodos , Extractos Vegetales/administración & dosificación , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/etiología , Enfermedades Cardiovasculares/enzimología , Ciclooxigenasa 2/metabolismo , Fluorouracilo/administración & dosificación , Masculino , Miocardio/enzimología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Over the last few decades, substantial progress has been made towards the understanding of cardiovascular diseases. In-depth mechanistic insights have also provided opportunities to explore novel therapeutic targets and to discover new treatment regimens. Therapeutic enzymes are examples of such opportunities. The enzymes protect against a variety of cardiovascular diseases, however, even minor malfunctioning of these enzymes may lead to deleterious outcomes. Owing to their great versatility, the inhibition and activation of these enzymes are key regulatory approaches to counter the onset and progression of several cardiovascular impairments. While cardiovascular remedies are already available in excess and are efficacious, a comprehensive description of novel therapeutic enzymes to combat cardiovascular diseases would still be of great benefit. In the light of this, the regulation of functional activities of these enzymes also opens a new avenue for the treatment approaches to be employed. This review describes the importance of non-conventional enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), phosphodiesterase (PDE), arginase, superoxide dismutase (SOD), thioredoxin reductase (TXNRD) and selenoprotein T (SELENOT), cytochrome b5 reductase 3 (CYB5R3), epoxide hydrolase (EHs), xanthine oxidoreductase (XOR), matrix metalloprotease (MMPs), and dopamine beta hydroxylase (DBH), as potential candidates in several cardiovascular disorders while highlighting some of the recently targeted therapeutic enzymes in cardiovascular diseases. We also discuss the role of intrinsic antioxidant defense system involved in cardioprotection followed by addressing some of the clinical investigations considering the use of antioxidant as a preferred therapy of cardiovascular complications.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/enzimología , Terapia Molecular Dirigida , Antioxidantes , Arginasa , Cardiotónicos , Enfermedades Cardiovasculares/etiología , Citocromo-B(5) Reductasa , Dopamina beta-Hidroxilasa , Epóxido Hidrolasas , Femenino , Humanos , Masculino , Metaloproteinasas de la Matriz , Persona de Mediana Edad , NADPH Oxidasas , Hidrolasas Diéster Fosfóricas , Selenoproteínas , Superóxido Dismutasa , Reductasa de Tiorredoxina-Disulfuro , Xantina DeshidrogenasaRESUMEN
The lysyl oxidase (LOX) family of enzymes catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin in the initiation step of the formation of covalent cross-linkages, an essential process for extracellular matrix (ECM) maturation. Elevated LOX expression levels leading to increased LOX activity is associated with diverse pathologies including fibrosis, cancer, and cardiovascular diseases. Different protocols have been so far established to detect and quantify LOX activity from tissue samples and cultured cells, all of them showing advantages and drawbacks. This review article presents a critical overview of the main features of currently available methods as well as introduces some recent technologies called to revolutionize our approach to LOX catalysis.
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Pruebas de Enzimas/métodos , Proteína-Lisina 6-Oxidasa/metabolismo , Animales , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Enfermedades Cardiovasculares/enzimología , Pruebas de Enzimas/instrumentación , Humanos , Neoplasias/enzimología , Imagen Óptica/instrumentación , Imagen Óptica/métodos , Proteína-Lisina 6-Oxidasa/análisisRESUMEN
Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.
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Enzimas/metabolismo , Metaloproteínas/metabolismo , Zinc/deficiencia , Zinc/metabolismo , Esclerosis Amiotrófica Lateral/enzimología , Antiinflamatorios/metabolismo , Antioxidantes/metabolismo , Apoptosis , Asma/enzimología , Anhidrasas Carbónicas/metabolismo , Enfermedades Cardiovasculares/enzimología , Homeostasis , Humanos , Sistema Inmunológico , Micronutrientes/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/enzimología , OligoelementosRESUMEN
Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.
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Enfermedades Cardiovasculares/prevención & control , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Ciclooxigenasa 2/metabolismo , Quercetina/uso terapéutico , Animales , Antioxidantes/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/enzimología , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Humanos , Osteoartritis/tratamiento farmacológico , Medición de Riesgo , Factores de RiesgoRESUMEN
The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.
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COVID-19/complicaciones , Enfermedades Cardiovasculares/virología , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/enzimología , COVID-19/etiología , COVID-19/fisiopatología , COVID-19/terapia , Factores de Riesgo Cardiometabólico , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/fisiopatología , Ensayos Clínicos como Asunto , Humanos , Inflamación/complicaciones , Inflamación/virología , Microcirculación , Caracteres Sexuales , Síndrome Post Agudo de COVID-19RESUMEN
Among reactive oxygen species, superoxide mediates the critical vascular redox signaling, resulting in the regulation of the human cardiovascular system. The reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) is the source of superoxide and relates to the crucial intracellular pathology and physiology of vascular smooth muscle cells, including contraction, proliferation, apoptosis, and inflammatory response. Human vascular smooth muscle cells express NOX1, 2, 4, and 5 in physiological and pathological conditions, and those enzymes play roles in most cardiovascular disorders caused by hypertension, diabetes, inflammation, and arteriosclerosis. Various physiologically active substances, including angiotensin II, stimulate NOX via the cytosolic subunits' translocation toward the vascular smooth muscle cell membrane. As we have shown, some pathological stimuli such as high glucose augment the enzymatic activity mediated by the phosphatidylinositol 3-kinase-Akt pathway, resulting in the membrane translocation of cytosolic subunits of NOXs. This review highlights and details the roles of human vascular smooth muscle NOXs in the pathophysiology and clinical aspects. The regulation of the enzyme expressed in the vascular smooth muscle cells may lead to the prevention and treatment of human cardiovascular diseases.
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Enfermedades Cardiovasculares/enzimología , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , NADPH Oxidasas/metabolismo , Estrés Oxidativo , Superóxidos/metabolismo , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Hemodinámica , Humanos , Isoenzimas , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/patologíaRESUMEN
OBJECTIVE: According to reports, liver enzymes might play a role in the incidence and development of cardiometabolic diseases such as metabolic syndrome (MetS), hypertension (HTN), and cardiovascular diseases (CVD). We conducted a study to investigate this hypothesis among the Iranian Kurdish population. METHODS: We analyzed data from the baseline phase of the Ravansar noncommunicable disease (RaNCD) cohort. The association between liver enzymes (ALT, AST, ALT/AST ratio, GGT, and ALP) with cardiometabolic disease risk factors was investigated by multiple linear regression. The odds ratio of cardiometabolic diseases in each quartile category of liver enzyme concentration was estimated using multivariable logistic regression. RESULTS: The mean age of participants was 47.3 ± 4.1 years (48.1 years in males and 51.8 years in females). In the adjusted model, all enzymes were positively associated with MetS, HTN, and CVD risk factors except for the ALT/AST ratio with SBP and DBP. In the adjusted model, subjects in the fourth quartile for GGT, ALT/AST ratio, ALT, ALP, and AST had 3.29-, 2.94-, 2.45-, 2.00-, and 1.19-fold increased risk for MetS compared with subjects in the first quartile. Increased levels of GGT and ALP were positively associated with the risk of HTN (ORs = 1.33, 95%CI = 1.03-1.71 for GGT; ORs = 1.32, 95%CI = -1.68 for ALP). An increased GGT level was significantly associated with CVD (ORs = 1.54, 95%CI = 1.03-1.68). Within the normal range quartile, ALT had a significant correlation with the incidence of MetS. CONCLUSION: According to the present study, the levels of liver enzymes could be considered for early diagnosis of MetS, HTN, and CVD.
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Enfermedades Cardiovasculares/enzimología , Hígado/enzimología , Adulto , Anciano , Presión Sanguínea , Enfermedades Cardiovasculares/epidemiología , Femenino , Humanos , Hipertensión/enzimología , Hipertensión/epidemiología , Incidencia , Irán/epidemiología , Irán/etnología , Masculino , Síndrome Metabólico/enzimología , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Prevalencia , Estudios Prospectivos , Factores de Riesgo , FumarRESUMEN
Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.
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Esfingomielina Fosfodiesterasa/fisiología , Animales , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/terapia , Humanos , Neoplasias/enzimología , Neoplasias/terapia , Enfermedades del Sistema Nervioso/enzimología , Enfermedades del Sistema Nervioso/terapia , Enfermedades Respiratorias/enzimología , Enfermedades Respiratorias/terapia , Esfingomielina Fosfodiesterasa/química , Esfingomielina Fosfodiesterasa/clasificaciónRESUMEN
CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (either viral and host proteins). CK2 is also considered an emerging target for neurological diseases, inflammation and autoimmune disorders, diverse ophthalmic pathologies, diabetes, and obesity. In addition, CK2 activity has been associated with cardiovascular diseases, as cardiac ischemia-reperfusion injury, atherosclerosis, and cardiac hypertrophy. The hypothesis of considering CK2 inhibition for cystic fibrosis therapies has been also entertained for many years. Moreover, psychiatric disorders and syndromes due to CK2 mutations have been recently identified. On these bases, CK2 is emerging as an increasingly attractive target in various fields of human medicine, with the advantage that several very specific and effective inhibitors are already available. Here, we review the literature on CK2 implication in different human pathologies and evaluate its potential as a pharmacological target in the light of the most recent findings.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Enfermedades Cardiovasculares , Quinasa de la Caseína II , Fibrosis Quística , Oftalmopatías , Trastornos Mentales , Inhibidores de Proteínas Quinasas/uso terapéutico , SARS-CoV-2 , COVID-19/enzimología , COVID-19/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/genética , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/enzimología , Fibrosis Quística/genética , Oftalmopatías/tratamiento farmacológico , Oftalmopatías/enzimología , Oftalmopatías/genética , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/enzimología , Trastornos Mentales/genética , Mutación , Fosforilación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The cellular damage caused by redox imbalance is involved in the pathogenesis of many cardiovascular diseases. Besides, redox imbalance is related to the alteration of protein acetylation processes, causing not only chromatin remodeling but also disturbances in so many processes where protein acetylation is involved, such as metabolism and signal transduction. The modulation of acetylases and deacetylases enzymes aids in maintaining the redox homeostasis, avoiding the deleterious cellular effects associated with the dysregulation of protein acetylation. Of note, regulation of protein acetylation has shown protective effects to ameliorate cardiovascular diseases. For instance, HDAC inhibition has been related to inducing cardiac protective effects and it is an interesting approach to the management of cardiovascular diseases. On the other hand, the upregulation of SIRT protein activity has also been implicated in the relief of cardiovascular diseases. This review focuses on the major protein acetylation modulators described, involving pharmacological and bioactive compounds targeting deacetylase and acetylase enzymes contributing to heart protection through redox homeostasis.
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Acetilación/efectos de los fármacos , Enfermedades Cardiovasculares/enzimología , Corazón/fisiología , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Miocardio/metabolismo , Oxidación-Reducción , Sustancias Protectoras/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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Alanina Transaminasa/genética , Fosfatasa Alcalina/genética , Enfermedades Cardiovasculares/genética , Hígado/enzimología , Enfermedades Metabólicas/genética , gamma-Glutamiltransferasa/genética , Anciano , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Enfermedades Cardiovasculares/enzimología , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Regulación Enzimológica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Humanos , Resistencia a la Insulina/genética , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Masculino , Análisis de la Aleatorización Mendeliana , Enfermedades Metabólicas/enzimología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca , gamma-Glutamiltransferasa/sangreRESUMEN
Neuraminidase, also known as sialidase, is ubiquitous in animals and microorganisms. It is predominantly distributed in the cell membrane, cytoplasmic vesicles, and lysosomes. Neuraminidase generally recognizes the sialic acid glycosidic bonds at the ends of glycoproteins or glycolipids and enzymatically removes sialic acid. There are four types of neuraminidases, named as Neu1, Neu2, Neu3, and Neu4. Among them, Neu1 is the most abundant in mammals. Recent studies have revealed the involvement of Neu1 in several diseases, including cardiovascular diseases, diabetes, cancers, and neurological disorders. In this review, we center the attention to the role of Neu1 in cardiovascular diseases, including atherosclerosis, ischemic myocardial injury, cerebrovascular disease, congenital heart disease, and pulmonary embolism. We also summarize inhibitors from Chinese herbal medicines (CHMs) in inhibiting virus neuraminidase or human Neu1. Many Chinese herbs and Chinese herb preparations, such as Lonicerae Japonicae Flos, Scutellariae Radix, Yupingfeng San, and Huanglian Jiedu Decoction, have neuraminidase inhibitory activity. We hope to highlight the emerging role of Neu1 in humans and potentially titillate interest for further studies in this area.