ABSTRACT
High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NT-proBNP as the main marker of heart failure on adiponectin using Mendelian randomisation. Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial). The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m2. Per five µg/mL higher adiponectin, the E/A ratio was -0.05 (95 % CI: -0.10, -0.01) lower, left ventricle ejection fraction was -0.5 % (95 % CI: -1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: -0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher. With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies.
Subject(s)
Adiponectin/physiology , Heart/physiology , Mendelian Randomization Analysis , Aged , Cross-Sectional Studies , Female , Heart Failure/physiopathology , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/metabolism , Natriuretic Peptide, Brain/physiology , Peptide Fragments/metabolism , Peptide Fragments/physiology , Ventricular Function, LeftABSTRACT
Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2âimmune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.
Subject(s)
Cell Adhesion Molecules/physiology , Pruritus/etiology , Animals , Humans , Integrins/physiology , Natriuretic Peptide, Brain/physiology , Sensation , TRPA1 Cation Channel/physiologyABSTRACT
Natriuretic peptides (NP), especially B type (BNP) and its N-terminal pro-B type natriuretic peptide (NT-proBNP), have long been regarded as biomarkers of volume overload and tools to exclude heart failure in the general population. However, their role in end-stage kidney disease (ESKD) is less certain given that BNP and NT-proBNP are excreted by the kidney and so serum concentrations of NPs are nearly universally elevated compared to controls. Nevertheless, the accumulated evidence suggests thatserum concentrations of NPs in patients with ESKD show moderate or strong positive relationships with underlying heart disease, abnormal cardiac structure or function and mortality. Limited evidence also supports the role of BNP including NT-proBNP, ANP in some studies, rather than CNP or DNP in risk stratification among ESKD patients as well as the utility of BNP samplings pre- and post- hemodialysis. However, studies of the cut-off values of NPs have yielded inconsistent results, such that further large-scale studies are needed to clarify these issues. This review summarizes the pathophysiology and significance of NPs in ESKD patients, especially their potential role as risk stratification biomarkers in clinical management.
Subject(s)
Kidney Failure, Chronic/blood , Kidney Failure, Chronic/physiopathology , Natriuretic Peptides/blood , Natriuretic Peptides/physiology , Biomarkers/blood , Heart Failure/blood , Heart Failure/complications , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Natriuretic Peptide, Brain/blood , Natriuretic Peptide, Brain/metabolism , Natriuretic Peptide, Brain/physiology , Natriuretic Peptides/metabolism , Peptide Fragments/blood , Peptide Fragments/metabolism , Peptide Fragments/physiology , Prognosis , Renal Dialysis , Risk FactorsABSTRACT
As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure.
Subject(s)
Cellular Reprogramming , Heart Failure/physiopathology , Angiotensin Receptor Antagonists/therapeutic use , Atrial Natriuretic Factor/physiology , Cardiovascular Agents/therapeutic use , Electrophysiological Phenomena , Heart Failure/drug therapy , Heart Failure/metabolism , Humans , Myocardial Contraction , Myocardium/metabolism , Natriuretic Peptide, Brain/physiology , Neprilysin/therapeutic useABSTRACT
Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.
Subject(s)
Atrial Natriuretic Factor/metabolism , Heart Failure/metabolism , Myocytes, Cardiac/metabolism , Natriuretic Peptide, Brain/metabolism , Receptors, Guanylate Cyclase-Coupled/metabolism , Animals , Atrial Appendage/cytology , Atrial Fibrillation/metabolism , Atrial Natriuretic Factor/genetics , Atrial Natriuretic Factor/physiology , Atrial Remodeling , Biomarkers/metabolism , Cyclic GMP/metabolism , Diabetes Mellitus/metabolism , Fibrosis , Gene Expression Regulation, Developmental , Heart Atria/cytology , Humans , Hypertension/metabolism , Lipid Metabolism/physiology , Metabolic Syndrome/metabolism , Mice , Myocardium/metabolism , Myocardium/pathology , Natriuretic Peptide, Brain/genetics , Natriuretic Peptide, Brain/physiology , Obesity/metabolism , Peptide Fragments/metabolism , Prognosis , Protein Processing, Post-Translational , Pulmonary Arterial Hypertension/metabolism , Secretory Vesicles/metabolism , Ventricular Remodeling , Water-Electrolyte Balance/physiologyABSTRACT
Sepsis continues to be a leading public health burden in the United States and worldwide. With the increasing use of advanced laboratory technology, there is a renewed interest in the use of biomarkers in sepsis to aid in more precise and targeted decision-making. Natriuretic peptides have been increasingly recognized to play a role outside of heart failure. They are commonly elevated among critically ill patients in the setting of cardiopulmonary dysfunction and may play a role in identifying patients with sepsis and septic shock. There are limited data on the role of these biomarkers in the diagnosis, management, outcomes and prognosis of septic patients. This review seeks to describe the role of natriuretic peptides in fluid resuscitation, diagnosis of ventricular dysfunction and outcomes and the prognosis of patients with sepsis. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) have been noted to be associated with left ventricular systolic and diastolic and right ventricular dysfunction in patients with septic cardiomyopathy. BNP/NT-proBNP may predict fluid responsiveness, and trends of these peptides may play a role in fluid resuscitation. Despite suggestions of a correlation with mortality, the role of BNP in mortality outcomes and prognosis during sepsis needs further evaluation.
A sepse persiste como importante sobrecarga à saúde pública nos Estados Unidos e em todo o mundo. Com o crescente uso de tecnologias laboratoriais, tem se renovado o interesse na utilização de biomarcadores na sepse, para auxiliar em um processo mais preciso e direcionado para tomadas de decisão. Os peptídeos natriuréticos vem sendo cada vez mais reconhecidos por seu papel que vai além da insuficiência cardíaca. Estes peptídeos estão comumente elevados em pacientes críticos que apresentam condições de disfunção cardiopulmonar e podem ter papel na identificação de pacientes com sepse e choque séptico. São poucos os dados disponíveis em relação ao papel destes biomarcadores no diagnóstico, no controle, nos desfechos e no prognóstico de pacientes sépticos. Esta revisão procura descrever o papel dos peptídeos natriuréticos na ressuscitação volêmica, no diagnóstico de disfunção ventricular, nos desfechos e no prognóstico de pacientes com sepse. Tem sido observado que o peptídeo natriurético tipo B (BNP) e o fragmento N-terminal do peptídeo natriurético tipo B (NT-proBNP) se associam com disfunção ventricular sistólica e diastólica, tanto esquerda quanto direita, em pacientes com cardiomiopatia séptica. O BNP e o NT-proBNP podem predizer a responsividade a volume, e as tendências de medidas seriadas destes peptídeos podem ser importantes na ressuscitação volêmica. A despeito da sugestão de correlação com mortalidade, o papel do BNP nos desfechos de mortalidade e prognóstico, durante a sepse, ainda necessita melhor avaliação.
Subject(s)
Natriuretic Peptide, Brain/physiology , Peptide Fragments/physiology , Sepsis , Fluid Therapy , Humans , Prognosis , Sepsis/complications , Sepsis/etiology , Sepsis/mortality , Sepsis/therapy , Shock, Septic/complications , Shock, Septic/etiology , Shock, Septic/mortality , Shock, Septic/therapy , Treatment Outcome , Ventricular Dysfunction, Left/etiologyABSTRACT
RESUMO A sepse persiste como importante sobrecarga à saúde pública nos Estados Unidos e em todo o mundo. Com o crescente uso de tecnologias laboratoriais, tem se renovado o interesse na utilização de biomarcadores na sepse, para auxiliar em um processo mais preciso e direcionado para tomadas de decisão. Os peptídeos natriuréticos vem sendo cada vez mais reconhecidos por seu papel que vai além da insuficiência cardíaca. Estes peptídeos estão comumente elevados em pacientes críticos que apresentam condições de disfunção cardiopulmonar e podem ter papel na identificação de pacientes com sepse e choque séptico. São poucos os dados disponíveis em relação ao papel destes biomarcadores no diagnóstico, no controle, nos desfechos e no prognóstico de pacientes sépticos. Esta revisão procura descrever o papel dos peptídeos natriuréticos na ressuscitação volêmica, no diagnóstico de disfunção ventricular, nos desfechos e no prognóstico de pacientes com sepse. Tem sido observado que o peptídeo natriurético tipo B (BNP) e o fragmento N-terminal do peptídeo natriurético tipo B (NT-proBNP) se associam com disfunção ventricular sistólica e diastólica, tanto esquerda quanto direita, em pacientes com cardiomiopatia séptica. O BNP e o NT-proBNP podem predizer a responsividade a volume, e as tendências de medidas seriadas destes peptídeos podem ser importantes na ressuscitação volêmica. A despeito da sugestão de correlação com mortalidade, o papel do BNP nos desfechos de mortalidade e prognóstico, durante a sepse, ainda necessita melhor avaliação.
ABSTRACT Sepsis continues to be a leading public health burden in the United States and worldwide. With the increasing use of advanced laboratory technology, there is a renewed interest in the use of biomarkers in sepsis to aid in more precise and targeted decision-making. Natriuretic peptides have been increasingly recognized to play a role outside of heart failure. They are commonly elevated among critically ill patients in the setting of cardiopulmonary dysfunction and may play a role in identifying patients with sepsis and septic shock. There are limited data on the role of these biomarkers in the diagnosis, management, outcomes and prognosis of septic patients. This review seeks to describe the role of natriuretic peptides in fluid resuscitation, diagnosis of ventricular dysfunction and outcomes and the prognosis of patients with sepsis. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) have been noted to be associated with left ventricular systolic and diastolic and right ventricular dysfunction in patients with septic cardiomyopathy. BNP/NT-proBNP may predict fluid responsiveness, and trends of these peptides may play a role in fluid resuscitation. Despite suggestions of a correlation with mortality, the role of BNP in mortality outcomes and prognosis during sepsis needs further evaluation.
Subject(s)
Humans , Peptide Fragments/physiology , Sepsis/complications , Sepsis/etiology , Sepsis/mortality , Sepsis/therapy , Natriuretic Peptide, Brain/physiology , Prognosis , Shock, Septic/complications , Shock, Septic/etiology , Shock, Septic/mortality , Shock, Septic/therapy , Treatment Outcome , Ventricular Dysfunction, Left/etiology , Fluid TherapySubject(s)
Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/physiology , Heart Failure/physiopathology , Female , Heart/physiopathology , Heart Failure/metabolism , Humans , Male , Natriuretic Peptide, Brain/metabolism , Natriuretic Peptide, Brain/physiology , Receptors, Atrial Natriuretic Factor/metabolismABSTRACT
B-type natriuretic peptide (BNP) was approved by the US Food and Drug Administration in 2001 for the treatment of heart failure. However, the effects of BNP in clinical applications are controversial and uncertain. Recently, study indicated that high BNP levels are associated with an increased risk of developing atrial fibrillation. In this study, we investigated the direct effects of BNP on TNF-α-induced atrial fibrosis mice, as well as its effects on human atrial myofibroblasts. We found that injecting TNF-α-induced mice with recombinant human BNP enhanced atrial fibrosis via matrix metalloproteinase-2 (MMP-2) expression and collagen accumulation. Furthermore, we found that BNP stimulated MMP-2 expression in human atrial myofibroblasts. Treatment of human atrial myofibroblasts with cycloheximide had no effect on this outcome; however, treatment of cells with MG132 enhanced BNP-induced MMP-2 expression, indicating that protein stability and inhibition of proteasome-mediated protein degradation pathways are potentially involved. Inhibition of SIRT1 significantly decreased BNP-induced MMP-2 expression. Additionally, confocal and coimmunoprecipitation data indicated that BNP-regulated MMP-2 expression are likely to be mediated through direct interaction with SIRT1, which is thought to deacetylate MMP-2 and to increase its protein stability in human atrial myofibroblasts. Finally, we confirmed that SIRT1 is expressed and cytoplasmically redistributed as well as colocalized with MMP-2 in mouse fibrotic atrial tissue. We suggest a possible fibrosis-promoting role of BNP in the atrium, although the antifibrotic properties of BNP in the ventricle have been reported in previous studies, and that the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis.
Subject(s)
Heart Atria/enzymology , Matrix Metalloproteinase 2/metabolism , Myofibroblasts/metabolism , Natriuretic Peptide, Brain/physiology , Acetylation , Animals , Fibrosis , Heart Atria/pathology , Humans , In Vitro Techniques , Mice , Myofibroblasts/enzymology , Sirtuin 1/metabolismSubject(s)
Heart Failure/metabolism , Myocardium/metabolism , Natriuretic Peptide, Brain/metabolism , Receptors, Atrial Natriuretic Factor/metabolism , Adult , Biomarkers/metabolism , Female , Heart Failure/pathology , Heart Failure/surgery , Heart Transplantation/trends , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/physiology , Receptors, Atrial Natriuretic Factor/physiology , Treatment OutcomeABSTRACT
Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP. Arterial relaxations to BNP were enhanced in diabetic rabbits. Indomethacin enhanced BNP-induced relaxation in control rabbits but showed no effect in diabetic rabbits. BNP-induced release of thromboxane A2 or prostacyclin was not different in both groups of animals. Iberiotoxin had no effect on relaxations to BNP in both groups of animals. Charybdotoxin displaced to the right the concentration-response curve to BNP in both group of animals, and inhibited BNP-induced relaxation only in diabetic rabbits. Glibenclamide did not modify the BNP-induced relaxations in control rabbits, but inhibited it in diabetic rabbits. These results suggest that diabetes induces hypereactivity of the rabbit renal artery to BNP by mechanisms that at least include (1) a reduced vasoconstrictor influence of arachidonic acid metabolites via cyclooxygenase 2, which is not related with changes in thromboxane A2 and prostacyclin release from the arterial wall and (2) a selectively increased modulatory activity of KATP and endothelial IKCa channels.
Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Natriuretic Peptide, Brain/physiology , Potassium Channels/physiology , Prostaglandins/physiology , Renal Artery/physiology , Animals , Male , Rabbits , VasodilationSubject(s)
Disease Management , Heart Failure/drug therapy , Natriuretic Peptide, Brain/physiology , Signal Transduction/physiology , Stroke Volume/physiology , Aminobutyrates/pharmacology , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds , Drug Combinations , Heart Failure/diagnosis , Heart Failure/physiopathology , Humans , Natriuretic Peptide, Brain/agonists , Signal Transduction/drug effects , Stroke Volume/drug effects , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , ValsartanABSTRACT
The primary purpose of the study was to evaluate whether a pericardiectomy (PERI) alters training- or myocardial infarction (MI)-induced left ventricular hypertrophy (LVH), chamber geometry, gene expression and/or running performance. Mice were randomized into 6 groups: naïve control (CONT)-sedentary (Sed), CONT-trained (Tr), PERI-Sed, PERI-Tr, MI-Sed and MI-Tr. MI mice also received a pericardiectomy as part of the MI surgical procedure. 10 weeks of treadmill running resulted in enhanced running performance-to-exhaustion in all 3 trained groups (CONT-Tr, PERI-Tr, MI-Tr) compared to sedentary cohorts (P<0.001). Training also resulted in similar increases in normalized LVH (LV/BW) in CONT-Tr and PERI-Tr mice. 2D-echocardiographic evaluation of LV internal chamber dimensions revealed that stroke diameter (SD) was larger in PERI compared to MI (P<0.01) but not CONT mice. Ventricular B-type natriuretic peptide mRNA (BNP) was elevated only in the 2 MI groups. Left ventricle ß1-adrenergic receptor (ß1-AR) and melusin transcripts both demonstrated an overall increase in trained compared to sedentary mice (both P<0.05). Additionally long-term pericardiectomy did not further enhance running performance or increase LV/BW in either sedentary or trained mice.
Subject(s)
Hypertrophy, Left Ventricular/physiopathology , Myocardial Infarction/physiopathology , Pericardiectomy , Physical Conditioning, Animal , Animals , Cytoskeletal Proteins/physiology , Echocardiography , Female , Gene Expression , Heart Ventricles/pathology , Male , Mice , Mice, Inbred C57BL , Muscle Proteins/physiology , Natriuretic Peptide, Brain/physiology , Random Allocation , Receptors, Adrenergic, beta/physiologyABSTRACT
OBJECTIVE: To analyze the clinical outcomes of emergency percutaneous intervention in acute myocardial infarction (AMI) during hospital, and to find the relevant risk factors for the prognosis and cardiac events. â© Methods: We retrospective analyzed the patient with acute ST segment elevation myocardial infarction, who was successfully performed emergency percutaneous coronary intervention (PCI) in the Cardiac Cath Lab of the Second Xiangya Hospital from January 2010 to December 2014. According to situation for cardiovascular events, patients were divided into 2 groups. The clinical factors were compared between the 2 groups.â© Results: The incidence of adverse event was 22% (67/304). By using t test and χ2 analysis, we found that Cr, NT-proBNP, HCT, WBC, age>75, Killip grade≥2, TIMI flow after PCI≤2, arrhythmia, multi-vessel lesion, ST-segment resolution≥50%, long D2B time are statistically different between the 2 groups. Logistic analysis revealed that HCT, NT-proBNP, Killip grade≥2, TIMI flow after PCI≤2, ST-segment resolution≥50%, long D2B time were important predictors for cardiac events in-hospital.â© Conclusion: HCT, NT-proBNP, Killip grade≥2, TIMI flow after PCI≤2, ST-segment resolution≥50%, long D2B time are important predictors for cardiac events in-hospital. The prognosis for AMI patient after emergency PCI could be improved and the incidence of cardiac event in hospital could be reduced if the high risk factors can be properly handled.
Subject(s)
Percutaneous Coronary Intervention/adverse effects , ST Elevation Myocardial Infarction/surgery , Treatment Outcome , Aged , Arrhythmias, Cardiac , Emergency Treatment/adverse effects , Female , Humans , Inpatients , Male , Natriuretic Peptide, Brain/physiology , Peptide Fragments/physiology , Prognosis , Retrospective Studies , Risk FactorsABSTRACT
Spinal itch transmission has been reported to be mediated by at least two neuronal populations in spinal dorsal horn, neurons expressing brain-natriuretic peptide (BNP) receptor (Npra) and gastrin-releasing peptide (GRP) receptor (GRPR). Although Npra-expressing neurons were shown to be upstream of GRPR- expressing neurons in spinal itch transmission, the roles of BNP and GRP in the spinal neurotransmission of histamine-dependent and -independent itch remains unclear. Using in vivo electrophysiology and behavior analysis, this study examined the responses of chloroquine (histamine-independent pruritogen)-responsive and histamine-responsive dorsal horn neurons to spinal applications of BNP and GRP. Electrophysiologically, 9.5% of chloroquine-responsive neurons responded to BNP, 33.3% to GRP, and 4.8% to both, indicating that almost half of chloroquine-responsive neurons were unresponsive to both BNP and GRP. In contrast, histamine-responsive neurons did not respond to spinal BNP application, whereas 30% responded to spinal GRP application, indicating that 70% of histamine-responsive neurons were unresponsive to both BNP and GRP. Behavioral analyses showed differences in the time-course and frequency of scratching responses evoked by intrathecal BNP and GRP. These findings provide evidence that most BNP-Npra and GRP-GRPR signaling involve different pathways of spinal itch transmission, and that multiple neurotransmitters, in addition to BNP and GRP, are involved in spinal itch transmission. The electrophysiological results also suggest that spinal BNP contributes little to histaminergic itch directly.
Subject(s)
Gastrin-Releasing Peptide/physiology , Natriuretic Peptide, Brain/physiology , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiology , Pruritus/physiopathology , Action Potentials , Animals , Chloroquine/administration & dosage , Gastrin-Releasing Peptide/administration & dosage , Histamine/administration & dosage , Male , Mice , Mice, Inbred C57BL , Natriuretic Peptide, Brain/administration & dosage , Pruritus/chemically inducedABSTRACT
B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. Our results showed that intrathecal administration of BNP (0.3-3 nmol) dose dependently elicited scratching responses, which could be blocked by the NPRA antagonist (Arg6,ß-cyclohexyl-Ala8,D-Tic16,Arg17,Cys18)-atrial natriuretic factor(6-18) amide (A71915). However, A71915 had no effect on intrathecal GRP-induced scratching. In contrast, pretreatment with a GRPR antagonist (D-Tpi6,Leu13ψ(CH2-NH)-Leu14)bombesin(6-14) (RC-3095) inhibited BNP-induced scratching. Immunostaining revealed that NPRA proteins colocalize with GRP, but not GRPR, in the superficial area of dorsal horn, whereas BNP proteins do not colocalize with either GRP or GRPR in the dorsal horn. Intradermal administration of ligands including endothelin-1, U-46619, bovine adrenal medulla 8-22, and Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL) increased scratching bouts at different levels of magnitude. Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that: 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord, and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch.
Subject(s)
Gastrin-Releasing Peptide/physiology , Natriuretic Peptide, Brain/physiology , Pruritus/metabolism , Receptors, Atrial Natriuretic Factor/physiology , Receptors, Bombesin/physiology , Spinal Cord/metabolism , Animals , Atrial Natriuretic Factor/pharmacology , Atrial Natriuretic Factor/therapeutic use , Bombesin/analogs & derivatives , Bombesin/pharmacology , Bombesin/therapeutic use , Gastrin-Releasing Peptide/antagonists & inhibitors , Male , Mice , Natriuretic Peptide, Brain/antagonists & inhibitors , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Pruritus/drug therapy , Receptors, Atrial Natriuretic Factor/antagonists & inhibitors , Receptors, Bombesin/antagonists & inhibitors , Spinal Cord/drug effects , Tetrahydroisoquinolines/pharmacology , Tetrahydroisoquinolines/therapeutic useABSTRACT
BACKGROUND: ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. In mouse trigeminal ganglion (TG), P2X3 receptor function is unexpectedly enhanced by pharmacological block of natriuretic peptide receptor-A (NPR-A), outlining a potential inhibitory role of endogenous natriuretic peptides in nociception mediated by P2X3 receptors. Lack of change in P2X3 protein expression indicates a complex modulation whose mechanisms for downregulating P2X3 receptor function remain unclear. RESULTS: To clarify this process in mouse TG cultures, we suppressed NPR-A signaling with either siRNA of the endogenous agonist BNP, or the NPR-A blocker anantin. Thus, we investigated changes in P2X3 receptor distribution in the lipid raft membrane compartment, their phosphorylation state, as well as their function with patch clamping. Delayed onset of P2X3 desensitization was one mechanism for the anantin-induced enhancement of P2X3 activity. Anantin application caused preferential P2X3 receptor redistribution to the lipid raft compartment and decreased P2X3 serine phosphorylation, two phenomena that were not interdependent. An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin. CONCLUSIONS: We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. Tonic inhibition of P2X3 receptor activity by BNP/NPR-A/PKG pathways occurs via two distinct mechanisms: P2X3 serine phosphorylation and receptor redistribution to non-raft membrane compartments. This novel mechanism of receptor control might be a target for future studies aiming at decreasing dysregulated P2X3 receptor activity in chronic pain.
Subject(s)
Natriuretic Peptide, Brain/physiology , Nociception/physiology , Receptors, Purinergic P2X3/metabolism , Animals , Chronic Pain/physiopathology , Down-Regulation , Ganglia, Sensory , Mice , Phosphorylation , Receptors, Atrial Natriuretic Factor/metabolism , Signal Transduction , Trigeminal GanglionABSTRACT
Chronic heart failure (CHF) is the final stage of various heart diseases, and is increasingly recognized as a major health problem in the elderly. Previous studies demonstrated that Btypenatriuretic peptide (BNP) is an established biomarker of CHF. Furthermore, BNP also regulates cell proliferation, differentiation and apoptosis. Recent evidence has revealed that BNP affects myocardial cell apoptosis during myocardial ischemiareperfusion injury. Long noncoding RNAs (lncRNAs) are emerging as novel molecular compounds involved in gene regulation, and have important roles in numerous human diseases. However, the mechanism underlying the BNP and lncRNA-induced regulation of myocardial cell apoptosis remains to be elucidated. The present study reported that lncRNA LSINCT5, upregulated by BNP, is able to regulate myocardial cell apoptosis via the activation of the caspase1/interleukin (IL)1ß signaling pathway. BNP-induced apoptosis of HCM cells was observed using flow cytometry, and involved caspase1. In addition, expression profiling using a human lncRNA polymerase chain reaction array revealed that LSINCT5 was highly expressed in BNP-treated myocardial cells, as compared with untreated cells. The role of lncRNA LSINCT5 in HCM cell apoptosis was also investigated. The results of the present study indicated that LSINCT5 silencing by small interfering RNA inhibits caspase1/IL1ß signaling, and suppresses apoptosis in BNP-treated HCM cells. Therefore, high expression levels of BNP promote the apoptosis of myocardial cells through the lncRNA LSINCT5 mediator, which activates the caspase1/IL1ß signaling pathway. These findings uncovered a novel pathogenic mechanism, and provided a potential therapeutic target for CHF.