Deterioration of diabetic nephropathy via stimulating secretion of cytokines by atrial natriuretic peptide.

BACKGROUND: Atrial natriuretic peptide (ANP) is a cardiovascular and metabolic hormone that has been identified recently as being associated with chronic kidney disease (CKD) without diabetes. Cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin (ADP) contribute to the development of type 2 diabetes (T2DM). The aim here was to investigate the relationships of ANP with cytokine levels and clinical variables in T2DM nephropathy patients. METHODS: A total of 81 participants with T2DM were recruited, including 37 patients with normoalbuminuria, 23 patients with microalbuminuria and 21 patients with macroalbuminuria. Serum concentrations of ANP and cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANP and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANP and the severity and presence of albuminuria. RESULTS: The macroalbuminuria patients exhibited higher plasma levels of ANP, TNF-α, IL-6, and ADP; higher serum creatinine (Cr) and blood urea nitrogen (BUN); and longer duration of diabetes mellitus (DM) than the patients with normoalbuminuria and microalbuminuria. Plasma ANP level was significantly associated with TNF-α (r = 0.876, p < 0.001), IL-6 (r = 0.816, p < 0.001) and ADP (r = 0.772, p < 0.001), independent of the duration of DM or the BUN concentration. CONCLUSION: ANP is higher in type 2 diabetes mellitus nephropathy subjects, especially those who have macroalbuminuria, which is associated with compensatory responses to inflammation.

Atrial natriuretic peptide promotes uterine decidualization and a TRAIL-dependent mechanism in spiral artery remodeling.

Atrial natriuretic peptide (ANP) is an important hormone in cardiovascular biology. It is activated by the protease corin. In pregnancy, ANP and corin promote uterine spiral artery remodeling, but the underlying mechanism remains unknown. Here we report an ANP function in uterine decidualization and TNF-related apoptosis-inducing ligand-dependent (TRAIL-dependent) death in spiral arterial smooth muscle cells (SMCs) and endothelial cells (ECs). In ANP- or corin-deficient mice, uterine decidualization markers and TRAIL expression were decreased, whereas in cultured human endometrial stromal cells (HESCs), ANP increased decidualization and TRAIL expression. In uterine spiral arteries from pregnant wild-type mice, SMC and EC loss occurred sequentially before trophoblast invasion. In culture, TRAIL from decidualized HESCs induced apoptosis in uterine SMCs, but not in ECs with low TRAIL receptor expression. Subsequently, cyclophilin B was identified from apoptotic SMCs that upregulated endothelial TRAIL receptor and caused apoptosis in ECs. These results indicate that ANP promotes decidualization and TRAIL expression in endometrial stromal cells, contributing to sequential events in remodeling of spiral arteries, including SMC death and cyclophilin B release, which in turn induces TRAIL receptor expression and apoptosis in ECs.

The Emerging Role of Atrial Natriuretic Peptide in Psychiatry.

INTRODUCTION: Atrial natriuretic peptide (ANP), composed by 28 amino-acids, is well known to modulate fluid and electrolyte homeostasis, the hypothalamic-pituitary-adrenal (HPA) axis activity and the immune system. Since ANP is produced in both heart and in the central nervous system (CNS), in the last years, increasing attention has been devoted to its possible role in neuropsychiatric disorders. Indeed, scattered data would indicate its possible role in anxiety, major depression, addictive behaviors, post-traumatic stress disorder and other stress-related disorders. Further, ANP has been hypothesized to represent one of the factors linking depression to cardiovascular health and the immune system. AIMS: Given the paucity of available information, the aim of this paper was to review the current literature on the role of ANP in the CNS and in the pathophysiology of different neuropsychiatric and stress-related conditions. DISCUSSION: Supporting data on ANP in psychiatric disorders are still limited to animal studies, or to a few "real" findings in patients gathered some decades ago that should be replicated in larger clinical samples. CONCLUSION: Further studies are necessary to understand the possible implications of ANP in neuropsychiatry, because potentially it might represent a new way for innovative psychopharmacological treatments in different conditions, all underlaid by hyperactive HPA axis.

Atrial Natriuretic Peptide Improves Neurite Outgrowth from Spiral Ganglion Neurons In Vitro through a cGMP-Dependent Manner.

The spiral ganglion neurons (SGNs) are the primary afferent neurons in the spiral ganglion (SG), while their degeneration or loss would cause sensorineural hearing loss. As a cardiac-derived hormone, atrial natriuretic peptide (ANP) plays a critical role in cardiovascular homeostasis through binding to its functional receptors (NPR-A and NPR-C). ANP and its receptors are widely expressed in the mammalian nervous system where they could be implicated in the regulation of multiple neural functions. Although previous studies have provided direct evidence for the presence of ANP and its functional receptors in the inner ear, their presence within the cochlear SG and their regulatory roles during auditory neurotransmission and development remain largely unknown. Based on our previous findings, we investigated the expression patterns of ANP and its receptors in the cochlear SG and dissociated SGNs and determined the influence of ANP on neurite outgrowth in vitro by using organotypic SG explants and dissociated SGN cultures from postnatal rats. We have demonstrated that ANP and its receptors are expressed in neurons within the cochlear SG of postnatal rat, while ANP may promote neurite outgrowth of SGNs via the NPR-A/cGMP/PKG pathway in a dose-dependent manner. These results indicate that ANP would play a role in normal neuritogenesis of SGN during cochlear development and represents a potential therapeutic candidate to enhance regeneration and regrowth of SGN neurites.

Cardiac foetal reprogramming: a tool to exploit novel treatment targets for the failing heart.

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.

Cardiac natriuretic peptides.

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.

Clínica neurológica en un cuadro respiratorio: cuando Na importa / Neurological symptoms in an acute respiratory pattern: when Na matters

La aparición de clínica neurológica en un cuadro respiratorio agudo, una vez descartadas hipoxia e hipercapnia secundarias a insuficiencia respiratoria grave, nos debe hacer pensar en una hiponatremia subyacente, formando parte de un síndrome de secreción inadecuada de hormona antidiurética (SIADH). Esta alteración hidroelectrolítica se ha considerado un factor de mal pronóstico en la evolución del proceso respiratorio, por lo que es deseable detectarla precozmente y corregirla. Presentamos el caso de un lactante que debutó con hipoactividad y pausas de apnea previas a la clínica respiratoria de una bronquiolitis

The appearance of neurological symptoms in an acute respiratory pattern, once hypoxia and hypercapnia are ruled out secondary to severe respiratory failure, should lead us to think about an underlying hyponatremia, forming part of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This hydroelectrolytic alteration has been considered a factor of poor prognosis in the evolution of the respiratory process, so it is desirable to detect it early and correct it. We present the case of an infant who debuted with hypoactivity and apnea pauses prior to the respiratory symptoms of bronchiolitis

Major depression and atrial natriuretic peptide: The role of adverse childhood experiences.

Atrial natriuretic peptide (ANP) exerts anxiolytic effects in animals and humans. Patients with anxiety, trauma-associated and depressive disorders exhibit lower ANP plasma levels compared to healthy individuals. However, the role of ANP in patients with major depressive disorder (MDD) with and without concomitant adverse childhood experiences (ACE) and in healthy individuals with and without ACE is not clear. We recruited a total of 93 women: 23 women with MDD and ACE, 24 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD, and 24 healthy women without ACE. ANP plasma levels were measured with a radioimmunoassay. The four groups did not differ in demographic and clinical variables. We found a positive correlation between age and plasma levels of ANP (r = .39; p < .001). After controlling for age, there was no significant main effect of MDD or ACE on ANP plasma levels, but a significant interaction between MDD and ACE such that ACE was associated with reduced basal ANP levels in the absence of MDD. We assume that low plasma ANP might be a consequence of ACE in the absence of current psychopathology. Therefore, future studies are needed to replicate our findings and to characterize the influencing factors of ACE on ANP more comprehensively, for example by including a comprehensive trauma and comorbidity anamnesis as well as cardiovascular state and risk factors.

[Atrial natriuretic peptide: its relationship with anxiety and depression]. / Péptido natriurético atrial: su relación con la ansiedad y la depresión.

The Atrial Natriuretic Peptide (ANP) is a hormone secreted by the heart, and, due to its mechanisms in the central nervous system, it is credited with a possible anxiolytic and stress-reducing effect. The aim of this study consisted of examining the values of ANP in adults and its relationship with anxiety and depression. An exploratory, observational and cross-sectional study was adopted. The sample was composed by 30 attending a Mental Health Service. The Beck Anxiety Inventory and the Beck Depression Inventory were applied, and a negative association between ANP values and the depressive state under Beck scale (p=0.017) was observed, more precisely lower ANP levels in patients with Beck's severe depression state. There were no relevant associations between ANP values and Beck's anxiety states. In order to reinforce this research topic, it is necessary to perform longitudinal studies, gather wider samples and include biological indicators for anxiety and depression as alpha-amylase and cortisol.

Midregional pro-atrial natriuretic peptide, an important member of the natriuretic peptide family: potential role in diagnosis and prognosis of cardiovascular disease.

Midregional pro-atrial natriuretic peptide (MR-proANP), first isolated in 1981, is a novel peptide with multiple biological functions, especially within the cardiovascular system. This peptide plays an important role in many processes, including natriuresis, diuresis, and other physiological and pathophysiological pathways in the human body. Several electronic databases (PubMed, EBSCO, Scopus, and ScienceDirect) were analyzed in the present literature review. The aim of this study was to elucidate the wide roles of MR-proANP, which can be analyzed because of the development of a new sandwich immunoassay, and to determine the possible diagnostic and prognostic implications of MR-proANP on cardiovascular disease and other disorders. The studies discussed in this literature review provide valuable data on the role of ANP in the pathogenesis, diagnostic process, prognosis, and potential therapeutic strategies for disease. Although ANP is mainly associated with cardiovascular disease, it may be used as a biomarker in diabetology, neurology, and metabolic disorders.

[Atrial natriuretic hormones and metabolic syndrome: recent advances]. / Hormones natriurétiques et syndrome métabolique : mise au point.

Natriuretic peptides are a group of hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C type (CNP), urodilatin and guanilyn. ANP (half-life: 2-4 min), is secreted by the atrium, BNP (half-life: 20 min) by the ventricle, CNP by the vascular endothelium, urodilatin by the kidney and guanylin by the intestine. These natriuretic peptides prevent water and salt retention through renal action, vasodilatation and hormonal inhibition of aldosterone, vasopressin and cortisol. These peptides also have a recently demonstrated metabolic effect through an increase of lipolysis, thermogenesis, beta cell proliferation and muscular sensitivity to insulin. Blood levels of these natriuretic peptides depend on "active NPR-A receptors/clearance NPR-C receptors", the last ones being abundant on adipocytes. Therefore, natriuretic peptides act as adipose tissue regulator and constitute a link between blood pressure and metabolic syndrome. They are used as markers and treatment of cardiac failure. Other applications are on going. BNP and NT-proBNP (inactive portion de la pro-hormone) are used as markers of cardiac failure since they have a longer half-life than ANP. BNP decrease is quicker and more important than that one of NT-ProBNP in case of improvement of cardiac failure. Chronic renal insufficiency and beta-blockers increase BNP levels. BNP measurement is useless under treatment with neprilysine inhibitors such as sacubitril, one of the neutral endopeptidases involved in catabolism of natriuretic peptides. The association sacubitril/valsartan is a new treatment of chronic cardiac failure, acting through the decrease of ANP catabolism.

Atrial Natriuretic Peptide Inhibits Spontaneous Contractile Activity of Lymph Nodes.

Atrial natriuretic peptide dose-dependently inhibited spontaneous phase and tonic activity of smooth muscle strips from the capsule of isolated bovine mesenteric lymph nodes. Pretreatment with L-NAME, diclofenac, and methylene blue had practically no effect on the peptide-induced relaxation responses. In contrast, glibenclamide significantly reduced the inhibitory effect of atrial natriuretic peptide. We suppose that the NO-dependent and cyclooxygenase signaling pathways are not involved in implementation of the inhibitory effects of atrial natriuretic peptide. ATP-sensitive K(+)-channels of the smooth muscle cell membrane are the last component in the signaling pathway leading to relaxation of smooth muscles of the lymph node capsule caused by atrial natriuretic peptide; activation of these channels leads to membrane hyperpolarization and smooth muscle relaxation.

Reduction in central venous pressure enhances erythropoietin synthesis: role of volume-regulating hormones.

AIMS: Erythropoiesis is a tightly controlled biological event, but its regulation under non-hypoxic conditions, however, remains unresolved. We examined whether acute changes in central venous blood pressure (CVP) elicited by whole-body tilting affect erythropoietin (EPO) concentration according to volume-regulating hormones. METHODS: Plasma EPO, angiotensin II (ANGII), aldosterone, pro-atrial natriuretic peptide (proANP) and copeptin concentrations were measured at supine rest and up to 3 h during 30° head-up (HUT) and head-down tilt (HDT) in ten healthy male volunteers. Plasma albumin concentration was used to correct for changes in plasma volume and CVP was estimated through the internal jugular vein (IJV) aspect ratio with ultrasonography. RESULTS: From supine rest, the IJV aspect ratio was decreased and increased throughout HUT and HDT respectively. Plasma EPO concentration increased during HUT (13%; P = 0.001, P for linear component = 0.017), independent of changes in albumin concentration. Moreover, ANGII and copeptin concentrations increased during HUT, while proANP decreased. The increase in EPO concentration during HUT disappeared when adjusted for changes in copeptin. During HDT, EPO, ANGII and copeptin concentrations remained unaffected while proANP increased. In regression analyses, EPO was positively associated with copeptin (ß = 0.55; 95% CI = 0.18, 0.93; P = 0.004) irrespective of changes in other hormones and albumin concentration. CONCLUSION: Reduction in CVP prompts an increase in plasma EPO concentration independent of hemoconcentration and hence suggests CVP per se as an acute regulator of EPO synthesis. This effect may be explained by changes in volume-regulating hormones.

Diagnosis and Treatment of Cerebral Salt Wasting Syndrome With Cryptococcal Meningitis in HIV Patient.

Hyponatremia is one of the most common electrolyte imbalances in HIV patients. The differential diagnosis may include hypovolemic hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and adrenal insufficiency. Here, we describe a case of hyponatremia secondary to cerebral salt wasting syndrome (CSWS) in an HIV patient with cryptococcal meningitis. A 52-year-old man with a history of diabetes and HIV was admitted for headache and found to have cryptococcal meningitis. He was also found to have asymptomatic hyponatremia. He had signs of hypovolemia, such as orthostatic hypotension, dry mucosa, decreased skin turgor, hemoconcentration, contraction alkalosis, and high BUN/Cr ratio. The laboratory findings revealed sodium of 125 mmol/L, potassium of 5.5 mmol/L, urine osmolality of 522 mOsm/kg, urine sodium of 162 mmol/L, and urine chloride of 162 mmol/L. We started normal saline for hypovolemia, each 1 L prior and after amphotericin therapy. However, hypovolemia did not improve significantly despite IV fluid. Cosyntropin stimulation test was negative, and renin level was 0.25 ng·mL·h, with the aldosterone level of <1 ng/dL, the serum brain natriuretic peptide of 15 pg/mL, and serum uric acid of 2.8 mg/dL. The diagnosis of CSWS was suspected, fludrocortisone was tried, and hypovolemia and hyponatremia improved. Cryptococcal meningitis in HIV patients can present with CSWS, and the distinction between CSWS and SIADH is important because the treatment for CSWS is different than that of SIADH. Both share a similar clinical picture except that CSWS presents with constant hypovolemia despite volume replacement. Salt tablets, normal saline, or fludrocortisone can be used for treatment.

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice.

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.

Pro Atrial Natriuretic Peptide (1-30) and 6-keto PGF1α Activity Affects Na(+) Homeostasis in Non-modulating Hypertension.

Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na(+) handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34±5y; 9 male) and 13 MHT (32±4y; 10male) were studied. Pro-ANP (1-30) PgI2, PRA and total exchangeable Na(+)24 (ENa(+)) were measured. Under low sodium intake, PRA (4.2±0.5ng.ml.h; p<0.05) and Pro-ANP (78.6±2pg/ml, p<0.05) were higher than in NMHT under (3.1±0.4ng.ml.h and 69.8±3 pg/ml). After 72h of high Na(+) intake, Pro-ANP (1-30) increased significantly only in MHT (82.1±3pg/ml, p<0.05). PgI2, under low sodium intake (1.83±0.2pg/24h), increased in MHT after 72h under high sodium (2.58±0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16±0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61±0.36 pg/24h; p=ns). A significant correlation between variations in ENa(+) and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa(+) in MHT (r=0.95; p<0.001) while a negative correlation between ENa(+) variations and ENa(+) (r=0.81, p<0.05) was observed in NMHT. ENa(+) variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling.

ANP-induced signaling cascade and its implications in renal pathophysiology.

The balance between vasoconstrictor/sodium-retaining and vasodilator/natriuretic systems is essential for maintaining body fluid and electrolyte homeostasis. Natriuretic peptides, such as atrial natriuretic peptide (ANP), belong to the vasodilator/natriuretic system. ANP is produced by the conversion of pro-ANP into ANP, which is achieved by a proteolytical cleavage executed by corin. In the kidney, ANP binds to the natriuretic peptide receptor-A (NPR-A) and enhances its guanylyl cyclase activity, thereby increasing intracellular cyclic guanosine monophosphate production to promote natriuretic and renoprotective responses. In the glomerulus, ANP increases glomerular permeability and filtration rate and antagonizes the deleterious effects of the renin-angiotensin-aldosterone system activation. Along the nephron, natriuretic and diuretic actions of ANP are mediated by inhibiting the basolaterally expressed Na(+)-K(+)-ATPase, reducing apical sodium, potassium, and protein organic cation transporter in the proximal tubule, and decreasing Na(+)-K(+)-2Cl(-) cotransporter activity and renal concentration efficiency in the thick ascending limb. In the medullary collecting duct, ANP reduces sodium reabsorption by inhibiting the cyclic nucleotide-gated cation channels, the epithelial sodium channel, and the heteromeric channel transient receptor potential-vanilloid 4 and -polycystin 2 and diminishes vasopressin-induced water reabsorption. Long-term ANP treatment may lead to NPR-A desensitization and ANP resistance, resulting in augmented sodium and water reabsorption. In mice, corin deficiency impairs sodium excretion and causes salt-sensitive hypertension. Characteristics of ANP resistance and corin deficiency are also encountered in patients with edema-associated diseases, highlighting the importance of ANP signaling in salt-water balance and renal pathophysiology.

Role of microtubules in attenuation of PepG-induced vascular endothelial dysfunction by atrial natriuretic peptide.

Apart from control of circulating fluid, atrial natriuretic peptide (ANP) exhibits anti-inflammatory effects in the lung. However, molecular mechanisms of ANP anti-inflammatory effects are not well-understood. Peripheral microtubule (MT) dynamics is essential for agonist-induced regulation of vascular endothelial permeability. Here we studied the role of MT-dependent signaling in ANP protective effects against endothelial cell (EC) barrier dysfunction and acute lung injury induced by Staphylococcus aureus-derived peptidoglican-G (PepG). PepG-induced vascular endothelial dysfunction was accompanied by MT destabilization and disruption of MT network. ANP attenuated PepG-induced MT disassembly, NFκB signaling and activity of MT-associated Rho activator GEF-H1 leading to attenuation of EC inflammatory activation reflected by expression of adhesion molecules ICAM1 and VCAM1. ANP-induced EC barrier preservation and MT stabilization were linked to phosphorylation and inactivation of MT-depolymerizing protein stathmin. Expression of stathmin phosphorylation-deficient mutant abolished ANP protective effects against PepG-induced inflammation and EC permeability. In contrast, siRNA-mediated stathmin knockdown prevented PepG-induced peripheral MT disassembly and endothelial barrier dysfunction. ANP protective effects in a murine model of PepG-induced lung injury were associated with increased phosphorylation of stathmin, while exacerbated lung injury in the ANP knockout mice was accompanied by decreased pool of stable MT. Stathmin knockdown in vivo reversed exacerbation of lung injury in the ANP knockout mice. These results show a novel MT-mediated mechanism of endothelial barrier protection by ANP in pulmonary EC and animal model of PepG-induced lung injury via stathmin-dependent control of MT assembly.

Natriuretic peptide system and the heart.

The natriuretic peptide (NP) family includes atrial (ANP), brain or B-type (BNP) and C-type NP (CNP). A huge number of experimental and clinical studies, published in the 1st decade of this century, have added further support to the hypothesis that endocrine function in the human heart is a relevant component of a complex network including endocrine, nervous and immune systems. The NP hormones constitute a well-integrated regulatory system and share a similar spectrum of biological actions, although there are some differences in biological potency between ANP, BNP and CNP. However, several important issues on this field need to be investigated further. The production, secretion and peripheral degradation pathways of both BNP and CNP should be clarified in detail. In particular, the hypothesis that the circulating plasma pool of the prohormone can function as a precursor of the active peptide hormone should be demonstrated definitively. Recent findings indicate that peripheral processing of circulating prohormones could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening up new perspectives even in the treatment of heart failure. This hypothesis suggests a novel pharmacological target for drugs inducing and/or modulating the maturation of the prohormone into active hormone.