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.
The Cells and Circuitry for Itch Responses in Mice Mishra, Santosh K.; Hoon, Mark A.
Science (American Association for the Advancement of Science),
05/2013, Letnik:
340, Številka:
6135
Journal Article
Recenzirano
Odprti dostop
Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response ...remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb -/- mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb -/- mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.
Processing of the brain natriuretic peptide (BNP) precursor, proBNP, is a convertase-dependent reaction that produces 2 molecules--the active BNP hormone and the N-terminal part of proBNP ...(NT-proBNP). Although proBNP was first described more than 15 years ago, very little is known about the cellular mechanism of its processing. The study of proBNP processing mechanisms is important, because processing impairments could be associated with the development of heart failure (HF).
The biochemical properties of recombinant proBNP and NT-proBNP and the same molecules derived from the blood of HF patients were analyzed by gel-filtration chromatography, site-directed mutagenesis, and different immunochemical methods with a panel of monoclonal antibodies (MAbs).
Part of the proBNP molecule (amino acid residues 61-76) located near the cleavage site was inaccessible to specific MAbs because of the presence of O-glycans, whereas the same region in NT-proBNP was completely accessible. We demonstrated that a convertase (furin) could effectively cleave deglycosylated (but not intact) proBNP. Of several mutant proBNP forms produced in a HEK 293 cell line, only the T71A variant was effectively processed in the cell.
Only proBNP that was not glycosylated in the region of the cleavage site could effectively be processed into BNP and NT-proBNP. Site-directed mutagenesis enabled us to ascertain the unique suppressing role of T71-bound O-glycan in proBNP processing.
Thirty years ago, De Bold et al. (20) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is ...now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction.
Summary Background The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute ...coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial. Methods Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15–90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov , number NCT00968708. Findings 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280–751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio HR 0·98, 95% CI 0·86–1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79–1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82–1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. Interpretation In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. Funding Takeda Development Center Americas.
To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease.
In a cross-sectional study of 575 subjects, serum adiponectin was ...compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged.
This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.
The pool of peptides composing a protein allows for its distinctive identification in a process named fingerprint (FP) analysis. Here, the FP concept is used to develop a method for the rational ...preparation of molecularly imprinted polymers (MIPs) for protein recognition. The fingerprint imprinting (FIP) is based on the following: (1) the in silico cleavage of the protein sequence of interest with specific agents; (2) the screening of all the peptide sequences generated against the UniProtKB database in order to allow for the rational selection of distinctive and unique peptides (named as epitopes) of the target protein; (3) the selected epitopes are synthesized and used as templates for the molecular imprinting process. To prove the principle, NT-proBNP, a marker of the risk of cardiovascular events, was chosen as an example. The in silico analysis of the NT-proBNP sequence allowed us to individuate the peptide candidates, which were next used as templates for the preparation of NT-pro-BNP-specific FIPs and tested for their ability to bind the NT-proBNP peptides in complex samples. Results indicated an imprinting factor, IF, of ∼10, a binding capacity of 0.5–2 mg/g, and the ability to rebind 40% of the template in a complex sample, composed of the whole digests of NT-proBNP.
The concept of natriuretic peptide guidance has been extensively studied in patients with chronic heart failure (HF), with only limited success. The effect of NT-proBNP (N-terminal probrain ...natriuretic peptide)-guided therapy in patients with acute decompensated HF using a relative NT-proBNP target has not been investigated. This study aimed to assess whether NT-proBNP-guided therapy of patients with acute decompensated HF using a relative NT-proBNP target would lead to improved outcomes compared with conventional therapy.
We conducted a prospective randomized controlled trial to study the impact of in-hospital guidance for acute decompensated HF treatment by a predefined NT-proBNP target (>30% reduction from admission to discharge) versus conventional treatment. Patients with acute decompensated HF with NT-proBNP levels >1700 ng/L were eligible. After achieving clinical stability, 405 patients were randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point was dual: a composite of all-cause mortality and HF readmissions in 180 days and the number of days alive out of the hospital in 180 days. Secondary end points were all-cause mortality within 180 days, HF readmissions within 180 days, and a composite of all-cause mortality and HF readmissions within 90 days.
Significantly more patients in the NT-proBNP-guided therapy group were discharged with an NT-proBNP reduction of >30% (80% versus 64%,
=0.001). Nonetheless, NT-proBNP-guided therapy did not significantly improve the combined event rate for all-cause mortality and HF readmissions (hazard ratio, 0.96; 95% confidence interval, 0.72-1.37;
=0.99) or the median number of days alive outside of the hospital (178 versus 179 days for NT-proBNP versus conventional patients,
=0.39). Guided therapy also did not significantly improve any of the secondary end points.
The PRIMA II trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) demonstrates that the guidance of HF therapy to reach an NT-proBNP reduction of >30% after clinical stabilization did not improve 6-month outcomes.
URL: http://www.trialregister.nl. Unique identifier: NTR3279.
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Plasma concentrations of B-type natriuretic peptide (BNP) or its amino terminal congener (NT-proBNP) are used for HF ...diagnosis and risk stratification. Because BNP concentrations are inexplicably lowered in obese patients, we investigated the relationship between proBNP glycosylation, plasma NT-proBNP, and body mass index (BMI) in HF patients.
Three assays were developed to distinguish between total proBNP (glycosylated plus nonglycosylated proBNP), proBNP not glycosylated at threonine 71 (NG-T71), and proBNP not glycosylated in the central region (NG-C). Intraassay and interassay CVs were <15%; limits of detection were <21 ng/L; and samples diluted in parallel.
Applying these assays and an NT-proBNP assay to plasma samples from 106 healthy volunteers and 238 HF patients determined that concentrations median (interquartile range) of proBNP, NG-T71, and NT-proBNP were greater in HF patients compared with controls 300 (44-664), 114 (18-254), and 179 (880-3459) ng/L vs 36 (18-229), 36 (18-175), and 40 (17-68) ng/L, respectively; all
< 0.012. NG-C was undetectable in most samples. ProBNP concentrations in HF patients with BMI more or less than 30 kg/m
were not different (
= 0.85), whereas HF patients with BMI >30 kg/m
had lower NT-proBNP and NG-T71 concentrations (
< 0.003) and higher proBNP/NT-proBNP and proBNP/NG-T71 ratios (
= 0.001 and
= 0.02, respectively) than those with BMI <30 kg/m
.
Increased BMI is associated with decreased concentrations of proBNP not glycosylated at T71. Decreased proBNP substrate amenable to processing could partially explain the lower NT-proBNP and BNP concentrations observed in obese individuals, including those presenting with HF.
Heart failure (HF) is the main cause of mortality worldwide, particularly in the elderly. N-terminal pro-brain natriuretic peptide (NT-proBNP) is the gold standard biomarker for HF diagnosis and ...therapy monitoring. It is determined in blood samples by the immunochemical methods generally adopted by most laboratories. Saliva analysis is a powerful tool for clinical applications, mainly due to its non-invasive and less risky sampling. This study describes a validated analytical procedure for NT-proBNP determination in saliva samples using a commercial Enzyme-Linked Immuno-Sorbent Assay. Linearity, matrix effect, sensitivity, recovery and assay-precision were evaluated. The analytical approach showed a linear behaviour of the signal throughout the concentrations tested, with a minimum detectable dose of 1 pg/mL, a satisfactory NT-proBNP recovery (95-110%), and acceptable precision (coefficient of variation ≤ 10%). Short-term (3 weeks) and long-term (5 months) stability of NT-proBNP in saliva samples under the storage conditions most frequently used in clinical laboratories (4, - 20, and - 80 °C) was also investigated and showed that the optimal storage conditions were at - 20 °C for up to 2.5 months. Finally, the method was tested for the determination of NT-proBNP in saliva samples collected from ten hospitalized acute HF patients. Preliminary results indicate a decrease in NT-proBNP in saliva from admission to discharge, thus suggesting that this procedure is an effective saliva-based point-of-care device for HF monitoring.
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