RESUMO
Caveolin-1 (Cav1) is a 22â kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. Scaffolds were originally described as SDS-resistant oligomers composed of 10-15 Cav1 monomers observable as 8S complexes by sucrose velocity gradient centrifugation. Recently, cryoelectron microscopy (cryoEM) and super-resolution microscopy have shown that 8S complexes are interlocking structures composed of 11 Cav1 monomers each, which further assemble modularly to form higher-order scaffolds and caveolae. In addition, Cav1 can act as a critical signaling regulator capable of direct interactions with multiple client proteins, in particular, the endothelial nitric oxide (NO) synthase (eNOS), a role believed by many to be attributable to the highly conserved and versatile scaffolding domain (CSD). However, as the CSD is a hydrophobic domain located by cryoEM to the periphery of the 8S complex, it is predicted to be enmeshed in membrane lipids. This has led some to challenge its ability to interact directly with client proteins and argue that it impacts signaling only indirectly via local alteration of membrane lipids. Here, based on recent advances in our understanding of higher-order Cav1 structure formation, we discuss how the Cav1 CSD may function through both lipid and protein interaction and propose an alternate view in which structural modifications to Cav1 oligomers may impact exposure of the CSD to cytoplasmic client proteins, such as eNOS.
Assuntos
Caveolina 1 , Transdução de Sinais , Animais , Humanos , Cavéolas/metabolismo , Caveolina 1/metabolismo , Caveolina 1/química , Membrana Celular/metabolismo , Microscopia Crioeletrônica , Óxido Nítrico Sintase Tipo III/metabolismo , Domínios ProteicosRESUMO
BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.
Assuntos
Diabetes Mellitus , Angiopatias Diabéticas , Lesões do Sistema Vascular , Animais , Humanos , Camundongos , Ratos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adiponectina/metabolismo , Diabetes Mellitus/genética , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/prevenção & controle , Angiopatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Epigênese Genética , Lesões do Sistema Vascular/genéticaRESUMO
The ability of cells to divide, migrate, relay signals, sense mechanical stimuli, and respond to stress all rely on nanoscale invaginations of the plasma membrane known as caveolae. The caveolins, a family of monotopic membrane proteins, form the inner layer of the caveolar coat. Caveolins have long been implicated in the generation of membrane curvature, in addition to serving as scaffolds for signaling proteins. Until recently, however, the molecular architecture of caveolins was unknown, making it impossible to understand how they operate at a mechanistic level. Over the past year, two independent lines of evidence - experimental and computational - have now converged to provide the first-ever glimpse into the structure of the oligomeric caveolin complexes that function as the building blocks of caveolae. Here, we summarize how these discoveries are transforming our understanding of this long-enigmatic protein family and their role in caveolae assembly and function. We present new models inspired by the structure for how caveolins oligomerize, remodel membranes, interact with their binding partners, and reorganize when mutated. Finally, we discuss emerging insights into structural differences among caveolin family members that enable them to support the proper functions of diverse tissues and organisms.
Assuntos
Cavéolas , Proteínas de Membrana , Cavéolas/metabolismo , Proteínas de Membrana/metabolismo , Caveolina 1/metabolismo , Membrana Celular/metabolismoRESUMO
Lung cancer is one of the most frequently diagnosed cancers worldwide. Due to its late diagnosis, it remains the leading cause of cancer-related deaths. Despite it is mostly associated to tobacco smoking, recent data suggested that genetic factors are of the highest importance. In this context, different processes meaningful for the development and progression of lung cancer such endocytosis, protein secretion and signal transduction, are controlled by membrane rafts. These highly ordered membrane domains contain proteins such as caveolins and flotillins, which were traditionally considered scaffold proteins but have currently been given a preponderant role in lung cancer. Here, we summarize current knowledge regarding the involvement of caveolins and flotillins in lung cancer from a molecular point of view.
Assuntos
Caveolinas , Neoplasias Pulmonares , Humanos , Caveolinas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microdomínios da MembranaRESUMO
Caveolae are an abundant, but enigmatic, plasma membrane feature of vertebrate cells. In this brief commentary, the authors attempt to answer some key questions related to the formation and function of caveolae based on round-table discussions at the first EMBO Workshop on Caveolae held in France in May 2019.
Assuntos
Cavéolas , Caveolinas , Animais , Membrana CelularRESUMO
Caveolins regulate myocardial substrate handling, survival signaling and stress-resistance, however control of expression is incompletely defined. We test how metabolic features of type 2 diabetes (T2D), and modulation of cell signaling, influence caveolins in H9c2 cardiomyoblasts. Cells were exposed to glucose (25 vs. 5 mM), insulin (100 nM) or palmitate (0.1 mM), individually or combined, and effects of adenylate cyclase (AC) activation (50 µM forskolin), focal adhesion kinase (FAK) or protein kinase C b2 (PKCß2) inhibition (1 µM FAK Inhibitor 14 or CGP-53353, respectively), or the polyunsaturated fatty acid (PUFA) α-linolenic acid (ALA; 10 µM) were tested. Simulated T2D (elevated glucose+insulin+palmitate) depressed caveolin-1 and -3 without modifying caveolin-2. Caveolin-3 repression was primarily palmitate dependent, whereas high glucose (HG) and insulin independently increased caveolin-3 (yet reduced expression when combined). Differential control was evident: baseline caveolin-3 was suppressed by FAK/PKCß2 and insensitive to AC activities, with baseline caveolin-1 and -2 suppressed by AC and insensitive to FAK/PKCß2. Forskolin and ALA selectively preserved caveolin-3 in T2D cells, whereas PKCb2 and FAK inhibition increased caveolin-3 under all conditions. Despite preservation of caveolin-3, ALA did not modify nucleosome content (apoptosis marker) or transcription of pro-inflammatory mediators in T2D cells. In summary: caveolin-1 and -3 are strongly repressed with simulated T2D, with caveolin-3 particularly sensitive to palmitate; intrinsic PKCb2 and FAK activities repress caveolin-3 in healthy and stressed cells; ALA, AC activation and PKCß2 inhibition preserve caveolin-3 under T2D conditions; and caveolin-3 changes with T2D and ALA appear unrelated to inflammatory signaling and extent of apoptosis.
RESUMO
Caveolae have been implicated in a wide range of critical physiological functions. In the past decade, the dominant role of cavin-1 in caveolae formation has been established, and it has been recognized as another master regulator for caveolae biology. Human patients with cavin-1 mutations develop lipodystrophy and muscular dystrophy and have some major pathological dysfunctions in fat tissue, skeleton muscle, heart, lung and other organs. Cavin-1 deficiency animal models consistently show similar phenotypes. However, the underlying molecular mechanisms remain to be elucidated. Recent studies have suggested many possible pathways, including mechanosensing, stress response, signal transduction, exosome secretion, and potential functions in the nucleus. Many excellent and comprehensive review articles already exist on the topics of caveolae structure formation, caveolins, and their pathophysiological functions. We will focus on recent studies using cavin-1 deficiency models, to summarize the pathophysiological changes in adipose, muscle, and other organs, followed by a summary of mechanistic studies about the roles of cavin-1, which includes caveolae formation, ribosomal RNA transcription, mechanical sensing, stress response, and exosome secretion. Further studies may help to elucidate the exact underlying molecular mechanism to explain the pathological changes observed in cavin-1 deficient human patients and animal models, so potential new therapeutic strategies can be developed.
Assuntos
Cavéolas/metabolismo , Exossomos/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Técnicas de Silenciamento de Genes , Humanos , Lipodistrofia/fisiopatologia , Proteínas de Membrana/genética , Camundongos , Distrofias Musculares/fisiopatologia , Mutação , RNA Ribossômico/genética , Proteínas de Ligação a RNA/genética , Transcrição GênicaRESUMO
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Patients with T2D have an increased risk to develop AD, while glucose metabolism abnormalities are frequent among AD patients. Epidemiological studies and the results of basic science point to possible shared pathophysiology between T2D and AD. Co-occurrence of diabetes mellitus and AD was noticed long time ago. However, more recent data reveal that comorbidity of AD and T2D occurs significantly more frequently than is expected by chance alone. In spite of the high importance of this association, the inter-relational mechanisms are unclear. The results of recent investigations indicate that caveolin-1 (CAV-1)-a small membrane protein involved in signaling pathways-may play an important role in this association. Preliminary results pointing to this role of CAV-1 were collected after examination of patients with AD. Subsequent investigation in an animal model confirmed these initial observations. The involvement of CAV-1 in T2D and AD may be mediated by cellular organelles, including mitochondria and endoplasmic reticulum.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Caveolina 1/metabolismo , Diabetes Mellitus Tipo 2/complicações , Doença de Alzheimer/complicações , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Proteínas tau/metabolismoRESUMO
Caveolae are 50-100â nm invaginations found within the plasma membrane of cells. Caveolae are involved in many processes that are essential for homeostasis, most notably endocytosis, mechano-protection, and signal transduction. Within these invaginations, the most important proteins are caveolins, which in addition to participating in the aforementioned processes are structural proteins responsible for caveolae biogenesis. When caveolin is misregulated or mutated, many disease states can arise which include muscular dystrophy, cancers, and heart disease. Unlike most integral membrane proteins, caveolin does not have a transmembrane orientation; instead, it is postulated to adopt an unusual topography where both the N- and C-termini lie on the cytoplasmic side of the membrane, and the hydrophobic span adopts an intramembrane loop conformation. While knowledge concerning the biology of caveolin has progressed apace, fundamental structural information has proven more difficult to obtain. In this mini-review, we curate as well as critically assess the structural data that have been obtained on caveolins to date in order to build a robust and compelling model of the caveolin secondary structure.
Assuntos
Caveolinas/química , Sequência de Aminoácidos , Animais , Humanos , Estrutura Secundária de Proteína , Homologia de Sequência de AminoácidosRESUMO
The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.
Assuntos
Cardiotônicos/farmacologia , Caveolinas/metabolismo , Coração/efeitos dos fármacos , Hélio/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Cardiotônicos/uso terapêutico , Cavéolas/efeitos dos fármacos , Cavéolas/metabolismo , Caveolinas/sangue , Caveolinas/genética , Células Cultivadas , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Hélio/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controleRESUMO
The vascular endothelial growth factor (VEGF) family of peptides and caveolins (CAVs) are reported to contribute, in early graft failure in patients, a coronary artery bypass grafting (CABG). To investigate the possible association of ultimate luminal occlusion to VEGFs and CAVs expression, a functional analysis (based on the molecular biology, bioinformatics, histology, and clinical studies) was performed. Twenty-four hundred and sixty-eight CABG patients diagnosed with multivessel stable coronary artery disease (CAD) were enrolled into prospective study and assigned to two subgroups: double- and triple-vessel CAD subjects. Distal parts of all the harvested saphenous vein (SV) and internal thoracic artery (ITA) segments were used for further tests. ITA graft failure did not differ between double-vessel and triple-vessel CAD patients. The number of SV occlusions was significantly higher in triple-vessel CAD subjects. The microarray analysis performed on SV and ITA samples obtained exclusively from triple-vessel CAD patients who developed early graft occlusion revealed 383 genes with increased and 301 genes with decreased expression in ITA samples as compared to SV grafts. This was followed by functional analysis of 'blood vessel development' group of genes. Average VEGF-C expression in ITA grafts was higher than in corresponding SV grafts; FLT4 expression was significantly higher in SV than in ITA transplants. VEGFR-3 and CAV3 expression demonstrated immunohistochemically in SMCs of the tunica media of SV grafts predicted their early restenosis in triple-vessel CAD patients. CAV2 protein expression in SMCs of ITA grafts indicated the risk of early graft failure both in double-vessel and triple-vessel CAD subjects.
Assuntos
Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Regulação da Expressão Gênica , Oclusão de Enxerto Vascular/genética , Fator C de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Idoso , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Feminino , Oclusão de Enxerto Vascular/diagnóstico , Oclusão de Enxerto Vascular/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Estudos Prospectivos , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Fator C de Crescimento do Endotélio Vascular/biossíntese , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Grau de Desobstrução VascularRESUMO
The identification of ancillary biomarkers useful to improve diagnosis is a major challenge for adipocytic liposarcoma (LPS), the most common type among soft tissue sarcomas affecting adulthood. Recent findings have reported the expression of some proteins belonging to Caveolin and Cavin families as a critical hallmark distinctive of the least aggressive, well-differentiated LPS tumors. These proteins are involved in the biogenesis, morphology and function of caveolae, minute bulb-shaped domains of the plasma membrane that play a crucial role in the adipose tissue by controlling hormone-dependent uptake of nutrients and contributing to the maintenance of tissue integrity. In light of this, in this paper we covered different topics, including metabolism, hypoxia and cell mechanoprotection, to outline the rationale for considering a deeper investigation of Caveolin and Cavin protein members in LPS neoplasms as an opportunity to identify pro-differentiating mechanisms that could counteract tumor growth.
Assuntos
Biomarcadores Tumorais/genética , Caveolina 1/genética , Lipossarcoma/genética , Proteínas de Ligação a RNA/genética , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/patologia , Cavéolas/metabolismo , Cavéolas/patologia , Diferenciação Celular/genética , Membrana Celular/genética , Membrana Celular/patologia , Humanos , Lipossarcoma/patologiaRESUMO
Caveolae are cholesterol enriched invaginations of the plasma membrane involved in a variety of processes, including glucose and fatty acids absorption, cell transduction and mechanoprotection. The biogenesis and function of caveolae depend on the activity of Caveolin (Cav-1, -2 and -3) and Cavin (Cavin-1, -2, -3 and -4) protein families. Since the membrane Cavin-2 protein was reported to play a key role in caveolae formation of adipocytes, in this work we have used a multidisciplinary approach to investigate its expression in liposarcoma (LPS), an adipocytic soft tissue sarcoma affecting adults. Data obtained through an in silico and immunohistochemical analysis suggest that Cavin-2, along with Cavin-1, Cav-1 and Cav-2, is mostly expressed in the least aggressive LPS subtype, namely well-differentiated LPS, while is almost undetectable in the more aggressive myxoid, pleomorphic and dedifferentiated LPS tumors. Accordingly, in vitro analysis confirmed that Cavin-2 expression increases in LPS tumor cell lines during differentiation as compared to proliferation, as detected by immunoblotting and immunofluorescence analysis. Overall, these data suggest that Cavin-2 represents a useful marker for discriminating the degree of differentiation in LPS tumors.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Fosfato , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Especificidade da EspécieRESUMO
Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described.
Assuntos
Caveolina 3/genética , Morte Súbita Cardíaca/etiologia , Variação Genética , Cardiomiopatias/complicações , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Caveolina 3/metabolismo , Canalopatias/complicações , Canalopatias/congênito , Canalopatias/genética , Canalopatias/fisiopatologia , Humanos , MutaçãoRESUMO
QRFP (RFamide) peptides are neuropeptides involved in food intake and adiposity regulation in rodents. We have previously shown that QRFP-43 (43RFa) and QRFP-26 (26RFa) inhibited isoproterenol (ISO)-induced lipolysis in adipocytes. However, the antilipolytic signaling pathways activated by QRFP peptides have not been investigated. In the present study, 3T3-L1 adipocytes were used to identify the main pathways involved in QRFP-43 decreasing ISO-induced lipolysis. Our results show that QRFP-43 reduced ISO-induced phosphorylation of perilipin A (PLIN) and hormone-sensitive lipase (HSL) on Ser660 by 43 and 25%, respectively, but increased Akt phosphorylation by 44%. However, the inhibition of phosphodiesterase 3B (PDE3B), a regulator of lipolysis activated by Akt, did not reverse the antilipolytic effect of QRFP-43. PDE3B inhibition reversed the decrease of Ser660 HSL phosphorylation associated with QRFP-43 antilipolytic effect. QRFP-43 also prevented PKC activation and ISO-induced Src kinases activation leading to the inhibition of the caveolin-1 (CAV-1) translocation on lipid droplets. Indeed, QRFP-43 attenuated phorbol 12-myristate 13-acetate-induced lipolysis and ISO-induced extracellular signal-regulated and Src kinases by 28, 37 and 48%, respectively. The attenuation of ISO-induced lipolysis by QRFP-43 was associated with a decrease of phosphorylated Ser660 HSL, PKA-catalytic (PKA-c) subunit and CAV-1 translocation on lipid droplets by 37, 50 and 46%, respectively. The decrease in ISO-induced CAV-1 and PKA-c translocation was associated with a reduction of PLIN phosphorylation by 44% in QRFP-43-treated adipocytes. These results suggest that QRFP-43 attenuated ISO-induced lipolysis by preventing the formation of an active complex on lipid droplets and the activation of Src kinases and PKC.
Assuntos
Adipócitos/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Caveolina 1/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Lipólise/efeitos dos fármacos , Peptídeos/farmacologia , Fosfoproteínas/metabolismo , Esterol Esterase/metabolismo , Células 3T3-L1 , Adipócitos/enzimologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática , Peptídeos e Proteínas de Sinalização Intercelular , Isoproterenol/farmacologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Camundongos , Complexos Multiproteicos , Perilipina-1 , Inibidores da Fosfodiesterase 3/farmacologia , Fosforilação , Proteína Quinase C/metabolismo , Transporte Proteico , Receptores Acoplados a Proteínas G/metabolismo , Serina , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Quinases da Família src/metabolismoRESUMO
Myocardial ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. Caveolae, caveolin-1 (Cav-1), and caveolin-3 (Cav-3) are essential for the protective effects of conditioning against myocardial I/R injury. Caveolins are membrane-bound scaffolding proteins that compartmentalize and modulate signal transduction. In this review, we introduce caveolae and caveolins and briefly describe the interactions of caveolins in the cardiovascular diseases. We also review the roles of Cav-1/-3 in protection against myocardial ischemia and I/R injury, and in conditioning. Finally, we suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included, herein, is potentially useful for the design of future studies and should advance the investigation of caveolins as therapeutic targets.
Assuntos
Caveolina 1/metabolismo , Caveolina 3/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , HumanosRESUMO
PURPOSE: During the postnatal stage, cardiovascular nitric oxide (NO) system and caveolins (cav) may be regulated differentially in response to hypovolemic state induced by water restriction. Our aim was to examine the effects of water restriction on NO synthases (NOS) and cav in the atria, ventricle and aorta of growing rats. METHODS: Male Sprague-Dawley rats aged 25 and 50 days were divided into (n = 15): WR: water restriction 3 days; WAL: water ad libitum 3 days. Systolic blood pressure, NOS activity and NOS/cav protein levels were measured. RESULTS: Dehydration induced a larger increase in SBP in WR25 group. Ventricular NOS activity, endothelial NOS (eNOS) and neuronal isoform (nNOS) of WR25 pups were increased, and both cav were decreased. In the WR50 group, NOS activity remained unchanged. In the atria, NOS activity, eNOS and nNOS decreased in WR25 associated with increased cav-1; in the WR50 group, NOS activity was increased without changes in NOS isoforms. In the aorta of WR25, NOS activity and inducible NOS (iNOS) were decreased; NOS activity was unchanged in WR50, despite the decreased levels of eNOS and increased iNOS, cav-1 and cav-3. CONCLUSIONS: NO system adjustments in cardiovascular system under osmotic stress in vivo depend on postnatal age, being eNOS and nNOS, the isoforms that determine NOS activity in cardiac tissue in 25-day-old pups. Changes in cav abundance during hypovolemic state may contribute to age-related NO production.
Assuntos
Sistema Cardiovascular/metabolismo , Caveolina 1/metabolismo , Caveolina 3/metabolismo , Desidratação , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Pressão Sanguínea , Caveolina 1/genética , Caveolina 3/genética , Endotélio/metabolismo , Átrios do Coração/metabolismo , Ventrículos do Coração/metabolismo , Hemodinâmica , Hipovolemia/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Pressão Osmótica , Ratos , Ratos Sprague-Dawley , Substâncias Reativas com Ácido TiobarbitúricoRESUMO
Breast cancer has become the most significant malignant tumor threatening women's lives. Caveolae are concave pits formed by invagination of the plasma membrane that participate in many biological functions of the cell membrane, such as endocytosis, cell membrane assembly, and signal transduction. In recent years, Caveolae family-related proteins have been found to be closely related to the occurrence and development of breast cancer. The proteins associated with the Caveolae family-related include Caveolin (Cav) and Cavins. The Cav proteins include Cav-1, Cav-2 and Cav-3, among which Cav-1 has attracted the most attention as a tumor suppressor and promoting factor affecting the proliferation, apoptosis, migration, invasion and metastasis of breast cancer cells. Cav-2 also has dual functions of inhibiting and promoting cancer and can be expressed in combination with Cav-1 or play a regulatory role alone. Cav-3 has been less studied in breast cancer, and the loss of its expression can form an antitumor microenvironment. Cavins include Cavin-1, Cavin-2, Cavin-3 and Cavin-4. Cavin-1 inhibits Cav-1-induced cell membrane tubule formation, and its specific role in breast cancer remains controversial. Cavin-2 acts as a breast cancer suppressor, inhibiting breast cancer progression by blocking the transforming growth factor (TGF-ß) signaling pathway. Cavin-3 plays an anticancer role in breast cancer, but its specific mechanism of action is still unclear. The relationship between Cavin-4 and breast cancer is unclear. In this paper, the role of Caveolae family-related proteins in the occurrence and development of breast cancer and their related mechanisms are discussed in detail to provide evidence supporting the further study of Caveolae family-related proteins as potential targets for the diagnosis and treatment of breast cancer.