RESUMEN
In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better understand distinctive features of these receptors, we carried out a phylogenetic analysis that revealed a mirror evolution of AT1 and AT2, each one split into two clades, separating fish from terrestrial receptors. It also revealed that hallmark mutations occurred at, or near, the sodium binding site in both AT1 and AT2. Electrostatics computations and molecular dynamics simulations support maintained sodium binding to human AT1 with slow ingress from the extracellular side and an electrostatic component of the binding free energy around -3kT, to be compared to around -2kT for human AT2 and the δ opioid receptor. Comparison of the sodium binding modes in wild type and mutated AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from fish to amniota. The unusual S7.46N mutation in AT1 is mirrored by a L3.36M mutation in AT2. In the presence of sodium, the N7.46 pattern in amniota AT1 stabilizes the inward orientation of N3.35 in the apo receptor, which should contribute to efficient N3.35 driven biased signaling. The M3.36 pattern in amniota AT2 favours the outward orientation of N3.35 and the receptor promiscuity. Both mutations have physiological consequences for the regulation of the renin-angiotensin system.
Asunto(s)
Angiotensina II , Receptor de Angiotensina Tipo 2 , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Filogenia , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Sodio , Vertebrados/genéticaRESUMEN
Telmisartan (TELM) is an angiotensin II (Ang II) type 1 receptor (Agtr1) antagonist, with partial agonism for Pparg, and has been shown to affect bone metabolism. Therefore, the aim of this study was to investigate the effects of TELM in the in vitro osteogenic differentiation of bone marrow-derived mesenchymal stromal cells (BMSC) from spontaneously hypertensive rats (SHRs). BMSC were obtained from male SHR, and the osteogenic medium (OM) was added to the cells concomitantly with TELM (0.005, 0.05, and 0.5 µM). Undifferentiated BMSC, in control medium (CM), showed an increased viability, while the addition of OM reduced this parameter, and TELM did not show cytotoxicity in the concentrations used. BMSC in OM had an alkaline phosphatase (ALP) activity peak at d10, which decreased at d14 and d21, and TELM reduced ALP at d10 in a dose-dependent manner. Mineralization was observed in the OM at d14, which intensified at d21, but was inhibited by TELM. Agtr1b was increased in the OM, and TELM inhibited its expression. TELM reduced Opn, Ocn, and Bsp and increased Pparg expression, and at the higher concentration TELM also increased the expression of adipogenic markers, Fabp4 and Adipoq. In addition, TELM 0.5 µM increased Irs1 and Glut4, insulin and glucose metabolism markers, known to be regulated by Pparg and to be related to adipogenic phenotype. Our data shows that TELM inhibited the osteogenic differentiation and mineralization of SHR BMSC, by favoring an adipogenic prone phenotype due to Pparg upregulation.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Telmisartán/farmacología , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Fosfatasa Alcalina/metabolismo , Animales , Calcificación Fisiológica/efectos de los fármacos , Matriz Extracelular/metabolismo , Masculino , PPAR gamma/metabolismo , Ratas Endogámicas SHR , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismoRESUMEN
Adverse environmental stress exposure at critical perinatal stages can alter cardiovascular development, which could persist into adulthood and develop a cardiovascular dysfunctional phenotype late in life. However, the underlying molecular mechanisms remain largely unknown. The present study provided a direct evidence that DNA methylation is a key epigenetic mechanism contributing to the developmental origins of adult cardiovascular disease. We hypothesized that DNA hypomethylation at neonatal stage alters gene expression patterns in the heart, leading to development of a cardiac ischemia-sensitive phenotype late in life. To test this hypothesis, a DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) was administered in newborn rats from postnatal day 1-3. Cardiac function and related key genes were measured in 2-week- and 2-month-old animals, respectively. 5-Aza treatment induced an age- and sex-dependent inhibition of global and gene-specific DNA methylation levels in left ventricles, resulting in a long-lasting growth restriction but an asymmetry increase in the heart-to-body weight ratio. In addition, treatment with 5-Aza enhanced ischemia and reperfusion-induced cardiac dysfunction and injury in adults as compared with the saline controls, which was associated with up-regulations of miRNA-181a and angiotensin II receptor type 1 & 2 gene expressions, but down-regulations of PKCε, Atg5, and GSK3ß gene expressions in left ventricles. In conclusion, our results provide compelling evidence that neonatal DNA methylation deficiency is a key mechanism contributing to differentially reprogram cardiac gene expression patterns, leading to development of a heart ischemia-sensitive phenotype late in life.
Asunto(s)
Metilación de ADN , Isquemia Miocárdica , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Metilasas de Modificación del ADN/metabolismo , Decitabina/farmacología , Femenino , Corazón/efectos de los fármacos , Corazón/fisiología , Masculino , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Fenotipo , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatologíaRESUMEN
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.
Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , COVID-19/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Autoinmunidad/efectos de los fármacos , Autoinmunidad/genética , COVID-19/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Receptores de Angiotensina/genética , Regeneración/efectos de los fármacos , Regeneración/genética , Regeneración/fisiología , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiología , Vulvodinia/inmunología , Vulvodinia/fisiopatología , Tratamiento Farmacológico de COVID-19RESUMEN
In pharmacogenomics, variable receptor phenotypes, resulting from genetic polymorphisms, are often described as a change in protein function or regulation observed upon exposure to a drug. However, in some instances, phenotypes are defined using a class of medications rather than individual drugs. This paradigm assumes that a variation associated with a drug response phenotype will retain the magnitude and direction of the effect for other drugs with the same mechanism of action. However, nonsynonymous polymorphisms may have ligand-specific effects. The purpose of this study was to investigate the potential for point mutations to asymmetrically affect the binding of different drugs to a common target. Ligand binding data from site-directed mutagenesis studies on five G-protein coupled receptors (beta-1 and -2 adrenergic, dopamine D2, angiotensin II and mu-opioid receptor) were collected and analyzed. Binding data from 81 studies for 253 ligands with 447 mutant proteins, including 10 naturally occurring human variants, were analyzed, yielding 1989 mutation-ligand pairs. Fold change in binding affinity for mutant proteins, relative to the wild-type, for different drugs was examined for ligand-specific effects, with a fold-change difference of one or more orders of magnitude between agents considered significant. Of the mutations examined, 49% were associated with ligand-specific effects. One human variant (T164I, beta-2 adrenergic receptor) showed ligand-specific effects for antiasthmatic agents. These results indicate that ligand-specific changes in binding are a possible consequence of missense mutations. This implies that caution needs to be exercised when grouping drugs together during design or interpretation of genotype-phenotype association studies.
Asunto(s)
Mutagénesis Sitio-Dirigida , Pruebas de Farmacogenómica , Receptores Acoplados a Proteínas G/genética , Receptores Opioides mu/genética , Antagonistas de Receptores de Angiotensina/farmacología , Estudios de Asociación Genética , Humanos , Ligandos , Polimorfismo Genético/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Receptores de Angiotensina/genética , Receptores de Dopamina D2/genética , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Mutación Silenciosa/genéticaRESUMEN
Inflammation is a crucial factor contributing to secondary brain injury after intracerebral haemorrhage (ICH). NLRP6, a member of nod-like receptors (NLRs) family, has been reported to participate in inflammation and host-defence in multiple diseases. Distinct from the other NLR family members, NLRP6 regulates inflammation in an inflammasome-dependent as well as an inflammasome-independent pathway. However, the role of NLRP6 in regulating signalling pathways during ICH is poorly understood. In the present study, we demonstrated that NLRP6 expression was upregulated after ICH, both in humans and in rats. Subsequently, we developed a rat model of ICH and found that NLRP6 knockdown reduced brain injury, alleviated inflammation, and suppressed autophagy following ICH. Further, results indicated that autophagy involved in NLRP6 mediated inflammation after ICH. Moreover, we found that NLRP6 mediated regulation of autophagy and inflammation was inflammasome-dependent. This study revealed the underlying molecular mechanism of NLRP6 in inflammation and highlights the therapeutic potential of targeting NLRP6 in secondary brain injury after ICH. KEY MESSAGES: ⢠NLRP6 was upregulated following ICH in humans and rats. ⢠NLRP6 knockdown reduced brain injury, alleviated inflammation, and suppressed autophagy following ICH. ⢠NLRP6 aggravated inflammation after ICH by activating autophagy. ⢠NLRP6 regulated inflammation and autophagy after ICH by activating inflammasome pathway.
Asunto(s)
Autofagia , Lesiones Encefálicas/etiología , Hemorragia Cerebral/complicaciones , Inflamación/etiología , Receptores de Angiotensina/genética , Receptores de Vasopresinas/genética , Animales , Biomarcadores , Lesiones Encefálicas/metabolismo , Hemorragia Cerebral/etiología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Humanos , Inmunohistoquímica , Inflamasomas/metabolismo , Inflamación/metabolismo , Ratas , Receptores de Angiotensina/metabolismo , Receptores de Vasopresinas/metabolismo , Transducción de SeñalRESUMEN
Cerebral stroke is a leading global cause for mortality and disability. However, its pathogenesis is still unclear. Most tripartite motif (TRIM) family proteins, including TRIM62, have E3 ubiquitin ligase activities, and have multiple functions in regulating cellular processes. Nevertheless, the effects of TRIM62 on cerebral stroke still remain vague. Here, we reported that TRIM62 expression was markedly up-regulated in oxygen and glucose deprivation (OGD)-treated microglial cells. After cerebral ischemia, significantly elevated expression of TRIM62 was detected in peri-infarct area of wild type (WT) mice. The TRIM62 knockout (KO) mice exhibited alleviated apoptosis and neuroinflammation in the ischemic brain, eventually attenuating the stroke outcomes. Both in vitro and in vivo studies showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome was dramatically activated in cerebral ischemia/reperfusion (I/R) conditions, while being ameliorated in TRIM62-KO mice, contributing to the suppression of neuroinflammatory response. Importantly, the in vitro experiments showed that OGD could induce the K63-ubiquitination of TRIM62 and the interaction between TRIM62 and NLRP3. In addition, adenovirus-regulated TRIM62 over-expression promoted the NLRP3 and nuclear factor κB (NF-κB) signaling, along with elevated interleukin-1ß (IL-1ß) and IL-18 transcriptional activities. Together, our results demonstrated that TRIM62 suppression was strongly protective in ischemic stroke through inhibiting NLRP3-regulated neuroinflammation.
Asunto(s)
Isquemia Encefálica/genética , Inflamación/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptores de Angiotensina/genética , Receptores de Endotelina/genética , Animales , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Técnicas de Inactivación de Genes , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Angiotensina/metabolismo , Receptores de Endotelina/metabolismo , UbiquitinaciónRESUMEN
G-protein-coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of ß-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a ß-arrestin-dependent luciferase assay, we characterize a GPCR-TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits ß-arrestin-dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II-mediated G-protein-associated second messenger accumulation, AT1R receptor phosphorylation, and ß-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin-dependent manner, preventing ß-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.
Asunto(s)
Receptores de Angiotensina/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Calcio/metabolismo , Calmodulina/genética , Calmodulina/metabolismo , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Receptores de Angiotensina/genética , Canales Catiónicos TRPV/genética , beta-Arrestinas/genética , beta-Arrestinas/metabolismoRESUMEN
BACKGROUND: It is unclear whether generics are as safe as brand-name drugs in cardiology. For public health surveillance purposes, we evaluated if switching from the brand-name losartan, valsartan, or candesartan impacted the occurrence of the following outcomes: emergency room (ER) consultations, hospitalizations, or death. STUDY DESIGN: This was a retrospective cohort study. METHODS: This study was conducted in the Quebec Integrated Chronic Disease Surveillance System, including healthcare administrative data of the population of Quebec, Canada. We included brand-name users of losartan, valsartan, or candesartan aged ≥ 66 years who had undergone ≥ 30 days of stable treatment on the brand-name drug prior to cohort entry (substitution time-distribution matching was used to prevent immortal time bias). Outcomes up to 1 year were compared between groups using multivariable Cox proportional hazards regression models (validity assumptions were verified). RESULTS: In our cohorts (losartan, n =15,783; valsartan, n =16,907; candesartan, n =26,178), mean age was 76-78 years, 59-66% were female, 90-92% had hypertension, and 13-15% had heart failure. Validity assumptions were violated for losartan only. For patients switched to generic valsartan, the hazard ratio (95% confidence interval) was 1.07 (0.99-1.14) for ER consultation, 1.26 (1.14-1.39) for hospitalization, and 1.01 (0.61-1.67) for death. The corresponding rates for candesartan were 1.00 (0.95-1.05), 0.96 (0.89-1.03), and 0.57 (0.37-0.88), respectively. CONCLUSIONS: We observed an increased risk of hospitalizations for patients switched to generic valsartan, and a decreased risk of death for patients switched to generic candesartan, compared with those who continued taking the brand-name drug. The differences between generic and brand-name drugs may lead to some differences in public health outcomes, but this safety signal must be further studied using other cohorts and settings.
Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Bencimidazoles/farmacología , Hipertensión/tratamiento farmacológico , Receptores de Angiotensina/metabolismo , Tetrazoles/farmacología , Valsartán/farmacología , Anciano , Compuestos de Bifenilo , Canadá , Estudios de Cohortes , Femenino , Humanos , Masculino , Salud Pública , Receptores de Angiotensina/genética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Few studies examined the effect of long-acting nitrates on renal function in chronic heart failure (CHF). Thus, we aimed to investigate the effect of long-acting nitrate on the expression of adrenoceptors (AR) and angiotensin II receptor (ATR) subtypes of the renal cortex, in rats with myocardial infarction-induced CHF. METHODS: Rats were randomly divided into the following groups: control, sham-operated, CHF, low- and high-dose nitrate, positive drug control (olmesartan), and high-dose of long-acting nitrate + olmesartan. Ultrasound echocardiography markers were compared, and the levels of AR subtypes, AT1R, and AT2R were measured using reverse transcription-polymerase chain reaction and western blot analysis. Histopathology of the kidney was determined on hematoxylin and eosin-stained sections. RESULTS: CHF significantly increased plasma renin activity (PRA) and angiotensin II levels, upregulated AT1R expression and downregulated α1A-, ß1-, ß2-AR, and AT2R expression compared to the sham control. High-dose nitrate or olmesartan alone, and especially in combination, decreased the levels of PRA and angiotensin II and downregulated the CHF-induced expression of AT1R, α1A-, ß1-, and ß2-AR, and AT2R. CHF resulted in significant impairment of the renal tissue, including inflammatory cells infiltration to the tubular interstitium and surrounding the renal glomerulus, and tubular necrosis, which was alleviated in all treatment groups to different degrees. CONCLUSIONS: Long-acting nitrates could reverse CHF-induced changes in AR and ATR subtypes in the kidney, and improve cardiac function to protect renal function. Compared with monotherapy, the combination of nitrates and olmesartan shows more significant benefits in regulating AR and ATR subtypes.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Dinitrato de Isosorbide/análogos & derivados , Corteza Renal/efectos de los fármacos , Infarto del Miocardio/complicaciones , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores de Angiotensina/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Imidazoles/farmacología , Dinitrato de Isosorbide/farmacología , Corteza Renal/metabolismo , Corteza Renal/fisiopatología , Masculino , Ratas Wistar , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos beta/genética , Receptores de Angiotensina/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Tetrazoles/farmacología , Factores de TiempoRESUMEN
NLRP6, the nucleotide oligomerization domain-like receptor family pyrin domain containing 6, has a substantiable effect on inflammation and host defense against microorganisms. In our previous study, NLRP6 promotes inflammation after cerebral I/R injury in a MCAO model. However, the effect of NLRP6 in different nerve cells subjected to OGD/R needs to be further understood. Here, evidence shows that the expression of NLRP6 is increased in different nerve cells subjected to OGD/R, and mainly expressed in astrocytes. NLRP6 may up-regulate inflammation factors (IL-1ß, Il-8) via the form of inflammasomes in astrocytes after OGD/R. Then, primary neuron-astrocyte co-culture model under OGD/R in vitro was performed, and we found that NLRP6 decreased the neurons viability and aggravated apoptosis of neurons. Mechanically, NLRP6 could induce pyroptosis to regulate the survival of neurons through activating caspase-1.
Asunto(s)
Astrocitos/metabolismo , Hipoxia de la Célula , Glucosa/deficiencia , Inflamasomas/metabolismo , Neuronas/metabolismo , Piroptosis , Receptores de Angiotensina/metabolismo , Receptores de Vasopresinas/metabolismo , Animales , Supervivencia Celular , Técnicas de Cocultivo , Microglía/metabolismo , Oxígeno , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Receptores de Vasopresinas/genéticaRESUMEN
A novel severe acute respiratory syndrome coronavirus, SARS-CoV-2, emerged in China in December 2019 and spread worldwide, causing more than 1.3 million deaths in 11 months. Similar to the human SARS-CoV, SARS-CoV-2 shares strong sequence homologies with a sarbecovirus circulating in Rhinolophus affinis bats. Because bats are expected to be able to transmit their coronaviruses to intermediate animal hosts that in turn are a source of viruses able to cross species barriers and infect humans (so-called spillover model), the identification of an intermediate animal reservoir was the subject of intense researches. It was claimed that a reptile (Ophiophagus hannah) was the intermediate host. This hypothesis was quickly ruled out and replaced by the pangolin (Manis javanica) hypothesis. Yet, pangolin was also recently exonerated from SARS-CoV-2 transmission to humans, leaving other animal species as presumed guilty. Guided by the spillover model, several laboratories investigated in silico the species polymorphism of the angiotensin I converting enzyme 2 (ACE2) to find the best fits with the SARS-CoV-2 spike receptor-binding site. Following the same strategy, we used multi-sequence alignment, 3-D structure analysis, and electrostatic potential surface generation of ACE2 variants to predict their binding capacity to SARS-CoV-2. We report evidence that such simple in silico investigation is a powerful tool to quickly screen which species are potentially susceptible to SARS-CoV-2. However, possible receptor binding does not necessarily lead to successful replication in host. Therefore, we also discuss here the limitations of these in silico approaches in our quest on the origins of COVID-19 pandemic.
Asunto(s)
COVID-19/inmunología , COVID-19/patología , Especificidad del Huésped/genética , Receptores de Angiotensina/genética , Origen de Réplica , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , Animales , China , Quirópteros/virología , Predisposición Genética a la Enfermedad , Humanos , Ophiophagus hannah/virología , Pandemias , Pangolines/virología , Polimorfismo de Nucleótido SimpleRESUMEN
Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln-/-) mice have high blood pressure and pathological remodeling of the aorta and die soon after birth. We hypothesized that decreasing blood pressure in Eln-/- mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln+/+ and Eln-/- mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln-/- LV pressure to values near Eln+/+ mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln-/- aorta. The changes in thickness and mechanical behavior in captopril-treated Eln-/- aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln-/- aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln-/- aortic behavior.
Asunto(s)
Aorta/crecimiento & desarrollo , Captopril/farmacología , Elastina/deficiencia , Estrés Mecánico , Remodelación Vascular/efectos de los fármacos , Animales , Animales Recién Nacidos , Aorta/efectos de los fármacos , Fenómenos Biomecánicos/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Desmosina/metabolismo , Elastina/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Hidroxiprolina/metabolismo , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismoRESUMEN
There is growing evidence that renin-angiotensin system (RAS) components have been involved in the development of various types of cancers, including prostate cancer. This article for the first time reports the impact of Ang1-9 and Ang3-7 on viability and proliferation, migration and invasion of epithelial prostate cells. The results of this study clearly show that Ang1-9 and Ang3-7 exert different/opposite effects on in vitro biological properties of prostate cells. It appears that Ang1-9 has pro-cancer activities via the ability to induce cell divisions, enhance cell motility and stimulate the expression of such genes as vascular endothelial growth factor (VEGF), hypoxia-inducible factors (HIF-1), vimentin (VIM) and REL proto-oncogene, NF-kB subunit (REL). On the contrary, Ang3-7 did not show any mitogenic activity. Furthermore, this peptide hormone limited the migration of PNT1A cells probably by downregulation of VEGF and VIM expression. Finally, it is worth noting that both angiotensins have the ability to modulate gene expression for angiotensin receptors. Unfortunately, we could not unequivocally identify the type of angiotensin receptor responsible for signal transduction pathway involved in PNT1A cell survival and proliferation. Undoubtedly, further research and testing in this area are necessary.
Asunto(s)
Angiotensina I/farmacología , Células Epiteliales/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Próstata/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Próstata/citología , Próstata/metabolismo , Proto-Oncogenes Mas , Receptores de Angiotensina/genética , Factor A de Crecimiento Endotelial Vascular/genética , Vimentina/genéticaRESUMEN
The NOD-like receptor protein 6 (NLRP6), an intracytoplasmic pattern recognition receptor in the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, influences the inflammation reaction. The role of NLRP6 in cerebral ischemia-reperfusion (I/R) injury in rats is unclear. We explore the function of NLRP6 in cerebral I/R injury. The investigators used a middle cerebral artery occlusion/reperfusion model (MCAO) to imitate ischemic injury. We found the peak expression of NLRP6 is in 48-h post-cerebral I/R injury. The expression of NLRP6 siRNA, as well as the expression of protein and mRNA, was detected by Western blot and qRT-PCR. The degree of IL-1ß and IL-18 was assessed by ELISA. After downregulating NLRP6, the expression of IL-1ß, IL-18, cleaved Caspase-1, and myeloperoxidase (MPO) were reduced. In HE and Nissl staining, pathological injury of brain tissue after downregulating NLRP6 was improved. NLRP6 siRNA decreased the NLRP6-ASC binding states by CO-IP. NRP6 has a pro-inflammatory effect in cerebral I/R injury, which may provide a new target for the treatment of cerebral I/R injury.
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Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Proteínas del Tejido Nervioso/fisiología , Receptores de Angiotensina/fisiología , Receptores de Vasopresinas/fisiología , Daño por Reperfusión/tratamiento farmacológico , Animales , Encéfalo/patología , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Caspasa 1/metabolismo , Regulación de la Expresión Génica , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Inflamación , Interleucina-18/biosíntesis , Interleucina-1beta/biosíntesis , Masculino , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Receptores de Vasopresinas/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Método Simple CiegoRESUMEN
Maternal high-fat diet (HFD) during pregnancy is linked to cardiovascular diseases in postnatal life. The current study tested the hypothesis that maternal HFD causes myocardial changes through angiotensin II receptor (AGTR) expression modulation in fetal and neonatal rat hearts. The control group of pregnant rats was fed a normal diet and the treatment group of pregnant rats was on a HFD (60% kcal fat). Hearts were isolated from embryonic day 21 fetuses (E21) and postnatal day 7 pups (PD7). Maternal HFD decreased the body weight of the offspring in both E21 and PD7. The ratio of heart weight to body weight was increased in E21, but not PD7, when compared to the control group. Transmission electron microscopy revealed disorganized myofibrils and effacement of mitochondria cristae in the treatment group. Maternal HFD decreased S-phase and increased G1-phase of the cellular cycle for fetal and neonatal cardiac cells. Molecular markers of cardiac hypertrophy, such as Nppa and Myh7, were found to be increased in the treatment group. There was an associated increase in Agtr2 mRNA and protein, whereas Agtr1a mRNA and AGTR1 protein were decreased in HFD fetal and neonatal hearts. Furthermore, maternal HFD decreased glucocorticoid receptors (GRs) binding to glucocorticoid response elements at the Agtr1a and Agtr2 promoter, which correlated with downregulation of GR in fetal and neonatal hearts. These findings suggest that maternal HFD may promote premature termination of fetal and neonatal cardiomyocyte proliferation and compensatory hypertrophy through intrauterine modulation of AGTR1 and AGTR2 expression via GR dependent mechanism.
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Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales Maternos , Miocardio/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores de Angiotensina/genética , Animales , Animales Recién Nacidos , Cardiomegalia/congénito , Cardiomegalia/embriología , Cardiomegalia/genética , Cardiomegalia/metabolismo , Células Cultivadas , Grasas de la Dieta/farmacología , Femenino , Feto/efectos de los fármacos , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/metabolismoRESUMEN
BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) has an important role in atherosclerosis. We investigated the effects of six RAAS gene polymorphisms on myocardial perfusion. METHODS AND RESULTS: We examined 810 patients with known or suspected coronary artery disease (CAD) using stress-rest myocardial single-photon emission computed tomography. Summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), transient ischemic dilation (TID), and lung/heart ratio (LHR) were recorded. The following gene polymorphisms were investigated: angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T and T174M, angiotensin II type 1 receptor (AT1R) A1166C, renin (REN) C5312T, and angiotensin II type 2 receptor (AT2R) C3123A. The heterozygotes or homozygotes on ACE D allele were 7.54 times more likely to have abnormal SSS, while the AGT (T174M) heterozygotes were 5.19 times more likely to have abnormal SSS. The homozygotes of ACE D had significantly higher values on TID and LHR, while the AGT (T174M) heterozygotes had higher values on TID. The AT1R heterozygotes had greater odds for having SSS ≥ 3. The patients carried AT1R homozygosity of C allele had significantly higher values on TID, while heterozygotes of AT1R had significantly higher values on LHR. CONCLUSIONS: Among the polymorphisms investigated, ACE D allele had the strongest association with abnormal myocardial perfusion.
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Angiotensinógeno/genética , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Receptores de Angiotensina/genética , Renina/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/fisiopatología , Circulación Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen de Perfusión Miocárdica , Sistema Renina-Angiotensina , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Sex differences in the presentation, outcome, and responses to treatment of systolic heart failure (HF) have been reported. In the present study, we examined the effect of sex on central neural mechanisms contributing to neurohumoral excitation and its peripheral manifestations in rats with HF. Male and female Sprague-Dawley rats underwent coronary artery ligation (CL) to induce HF. Age-matched rats served as controls. Ischemic zone and left ventricular function were similar 24 h and 4 wk after CL. Female rats with HF had a lower mortality rate and less hemodynamic compromise, pulmonary congestion, and right ventricular remodeling 4 wk after CL. Plasma angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine levels were increased in HF rats in both sexes, but AVP and norepinephrine levels increased less in female rats. In the hypothalamic paraventricular nucleus, a key cardiovascular-related nucleus contributing to neurohumoral excitation in HF, mRNA levels for the proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß as well as cyclooxygenase-2 and the ANG II type 1a receptor were increased in HF rats of both sexes, but less so in female rats. Angiotensin-converting enzyme 2 protein levels increased in female HF rats but decreased in male HF rats. mRNA levels of AVP were lower in female rats in both control and HF groups compared with the respective male groups. Activation of extracellular signal-regulated protein kinases 1 and 2 increased similarly in both sexes in HF. The results suggest that female HF rats have less central neural excitation and less associated hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. NEW & NOTEWORTHY Sex differences in the presentation and responses to treatment of heart failure (HF) are widely recognized, but the underlying mechanisms are poorly understood. The present study describes sex differences in the central nervous system mechanisms that drive neurohumoral excitation in ischemia-induced HF. Female rats had a less intense central neurochemical response to HF and experienced less hemodynamic compromise. Sex hormones may contribute to these differences in the central and peripheral adaptations to HF.
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Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Hipotálamo/metabolismo , Isquemia Miocárdica/fisiopatología , Animales , Arginina Vasopresina/sangre , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Masculino , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/metabolismo , Norepinefrina/sangre , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Factores Sexuales , Función VentricularRESUMEN
Sex hormones contribute to sex differences in blood pressure. Inappropriate activation of the renin-angiotensin system is involved in vascular dysfunction and hypertension. This study evaluated the role of androgens (testosterone) in angiotensin II (Ang II)-induced increase in blood pressure, vascular reactivity, and cardiac hypertrophy. Eight-week-old male Wistar rats underwent sham operation, castration, or castration with testosterone replacement. After 12 weeks of chronic changes in androgen status, Ang II (120 ng/kg per minute) or saline was infused for 28 days via subcutaneous miniosmotic pump, and changes in blood pressure was measured. Vascular reactivity and Ang II receptor levels were examined in mesenteric arteries. Heart weight, cardiac ANP mRNA levels, and fibrosis were also assessed. Ang II infusion increased arterial pressure in intact males. The Ang II-induced increase in hypertensive response was prevented in castrated males. Testosterone replacement in castrated males restored Ang II-induced hypertensive responses. Castration reduced vascular AT1R/AT2R ratio, an effect that was reversed by testosterone replacement. Ang II-induced hypertension was associated with increased contractile response of mesenteric arteries to Ang II and phenylephrine in intact and testosterone-replaced castrated males; these increases were prevented in castrated males. Ang II infusion induced increased left ventricle-to-body weight ratio and ANP mRNA expression, indicators of left ventricular hypertrophy, and fibrosis in intact and testosterone-replaced castrated males, and castration prevented the increase in these parameters caused by Ang II. This study demonstrates that testosterone plays a permissive role in development and maintenance of Ang II-induced vascular dysfunction, hypertension, and cardiac hypertrophy.
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Angiotensina II/farmacología , Cardiomegalia/inducido químicamente , Hipertensión/inducido químicamente , Testosterona/fisiología , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomegalia/sangre , Cardiomegalia/complicaciones , Cardiomegalia/fisiopatología , Hipertensión/sangre , Hipertensión/complicaciones , Hipertensión/patología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Orquiectomía , Ratas , Ratas Wistar , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Testosterona/sangreRESUMEN
The aim of the research was to assess the effect of nesfatin-1 on the structure, flexibility parameters, and expression of adropin, nesfatin-1, and angiotensin II receptor type 1 (AT1R) in the abdominal aorta in ovariectomized rats. Fragments of aortas were collected after euthanasia of female sham-operated (CONT) and ovariectomized Wistar rats (EXP), which were administered intraperitoneal injection of physiological saline (CONT, n = 7; EXP-O, n = 7) or nesfatin-1 (EXP-N, n = 7) in an amount of 2 µg/kg b.w. once a day for 8 weeks. The samples of aortas were collected for measurement of elasticity as well as histomorphometric, immunohistochemical, FTIR, and Raman spectroscopy analysis. The ovariectomy caused a significant increase in the thickness of the total wall and its particular layers in the aorta, in comparison to the CONT and EXP-N groups. However, the ovariectomy led to a decrease in the amount of elastin, collagen (mature, immature collagen, collagen maturity ratio 1660 - 1690 cm-1), and amides, with a simultaneous increase in lipids, especially in the tunica intima-media of the abdominal aorta compared to the other groups. The use of nesfatin-1 significantly increased the amount of collagen, elastin and amides with a simultaneous decrease in the amount of lipids and the expression of AT1R, adropin and nesfatin-1 in the abdominal aorta of ovariectomized rats. In conclusion, our study showed that the ovariectomy surgery induced changes in the abdominal aorta wall characteristic for aging females. Application of nesfatin-1 may prevent the negative consequences in the vessel wall structure in females in conditions of estrogen deficiency and prevent atherosclerotic changes in the cardiovascular system.