Atrial Natriuretic Peptide Production Research Articles

The endocrine basis of the cardio-renal axis: New perspectives regarding corin.

The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman etal. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor-/-). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman etal. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.

Atrial natriuretic peptide protects against gut barrier injury through PLC-γ1/ROS feedback loop in rats following traumatic hemorrhagic shock

Introduction The mechanisms underlying the protective effects of atrial natriuretic peptide (ANP) on the gut barrier during traumatic hemorrhagic shock (THS) remain elusive. This study aimed to explore the potential role of ANP in safeguarding against gut barrier dysfunction after THS, focusing on the PLC-γ1/ROS feedback loop. Methods In our THS rat model, we randomly allocated male Sprague-Dawley rats to receive intravenous ANP with or without a concurrent NADPH oxidase/p38 MAPK inhibitor during the shock phase. After 24 h, we assessed circulatory and jejunal ANP, ROS, intestinal tight junction proteins, and apoptosis to evaluate the effects of ANP on the gut barrier and its interplay with intestinal ANP and ROS. Rat small intestinal epithelial cells (IECs) were also treated with ANP and subjected to hypoxia/re-oxygenation injury, with or without PI3K/PLC inhibition, to elucidate the relationship between ANP/ROS signaling and PLC-γ1. Furthermore, we modulated PLC-γ1 expression in these IECs to examine its impact on ROS and ANP production. Results Intravenous ANP administration at 0.025 μg/kg/min during THS significantly increased intestinal ANP and ROS levels at 24 h. ANP treatment enhanced the expression of intestinal tight junction proteins and reduced IEC apoptosis. Inhibition of circulatory ROS diminished intestinal ANP levels, while suppression of circulatory ANP led to a reduction in intestinal ROS. Decreasing PLC-γ1 expression in hypoxia/re-oxygenation-treated IECs resulted in lower ROS and ANP levels, whereas augmenting PLC-γ1 expression did not alter these levels. Additionally, PI3K inhibition markedly decreased PLC-γ1 expression in these cells. Conclusion ANP-induced protection of the intestinal barrier in THS is mediated by an intrinsic PLC-γ1/ROS positive feedback loop. ANP preserves gut barrier integrity and reduces IEC apoptosis through this mechanism. Further studies are warranted to investigate the interaction between IECs and other cellular components within the PLC-γ1/ROS loop.

Pulmonary Arterial Hypertension Attenuates Vasoconstrictor Responses Caused by Activation of Alpha-1-Adrenoreceptors in the Systemic Circulation

Pulmonary arterial hypertension (PAH) accompanied by an arterial pressure increase in the pulmonary circulation, remodeling of pulmonary arteries and a change in its sensitivity to regulatory factors; PAH is accompanied by activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and increased production of atrial natriuretic peptide. The change in the sensitivity of the vessels of the systemic circulation (SC) to regulatory influences in PAH has not been investigated. Vasoconstrictor reactions in SC with monocrotaline (MCT) were studied in the work models of PAH in rats (Wistar, 350 ± 50 g, 4 months). Mean arterial pressure (MAP) was recorded against the background of a double autonomous blockade with the administration of the α1-adrenergic receptor agonist (α1-AR) phenylephrine (PE) to conscious rats at the start of experiment, then 2 and 4 weeks after the induction of PAH with MCT or saline injection for control animals. Registration of MAP under the action of PE was also performed during angiotensin-II (ATII) infusion. The maximal amplitude (Amax) of the change in MAP and the longest half-return time of MAP (T∆MAP1/2) to the baseline level in rats in response to the Phe injection were estimated. It was found that in response to PE, Amah did not change in rats with PAH, whereas in control animals it significantly increased. In rats with PAH 2 (n = 6) and 4 weeks after the induction of PAH with MCT, T∆MAP1/2 is significantly less than in control rats. ATII leads to delayed changes in T∆MAP1/2 in both control rats and rats with PAH. In rats with MAP, the potentiation with angiotensin T∆MAP1/2 is significantly less than in control rats. Thus, in animals with PAH, the ability of the resistive arteries of the systemic circulation to maintain tone in response to the activation of α1-AR decreases. In addition, PAH suppresses the ability of ATII to stimulate sympathetic responses in the SC. Firstly, in vivo, it has been demonstrated remodeling and changing the functional state of the pulmonary circulation leads to changes in the regulation of vascular tone of the systemic circulation.

Natriuretic peptide pathways in heart failure: further therapeutic possibilities.

The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.

Corin: A Key Mediator in Sodium Homeostasis, Vascular Remodeling, and Heart Failure

Simple SummaryAtrial natriuretic peptide (ANP) is an important hormone that regulates many physiological and pathological processes, including electrolyte and body fluid balance, blood volume and pressure, cardiac channel activity and function, inflammatory response, lipid metabolism, and vascular remodeling. Corin is a transmembrane serine protease that activates ANP. Variants in the CORIN gene are associated with cardiovascular disease, including hypertension, cardiac hypertrophy, atrial fibrillation, heart failure, and preeclampsia. The current data indicate a key role of corin-mediated ANP production and signaling in the maintenance of cardiovascular homeostasis. In this review, we discuss the latest findings regarding the molecular and cellular mechanisms underlying the role of corin in sodium homeostasis, uterine spiral artery remodeling, and heart failure.Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure.

Abstract 10140: Atrial Natriuretic Peptide Deficiency Associated with Greater Cardiometabolic Disease in Males

Introduction: The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in blood pressure (BP) and metabolic homeostasis through guanylyl cyclase receptor-A. While the role of ANP in cardiovascular disease (CVD) has been extensively investigated, its role in metabolic regulation has only recently emerged. A genetic variant of the ANP gene (rs5068), which increases production of ANP and NT-proANP, is associated with lower blood pressure (BP), reduced risk for hypertension and a decreased prevalence of obesity and metabolic syndrome. Hypothesis: We hypothesized that sex differences in ANP may have an important role in cardiometabolic disease together with cardiovascular (CV) morbidity and mortality. Methods: We studied 1176 subjects (age > 45 years) in the general population from Olmsted County MN. Plasma ANP molecular forms were quantified. Metabolic and cardiorenal parameters, and detailed medical records were reviewed. The cardiometabolic protective action of the ANP gene variant rs5068 was also assessed. Subjects were followed for all-cause mortality and morbidity for 12 years. Results: Plasma ANP molecular forms were significantly lower in males compared to females. Males had higher BMI and greater incidence of myocardial infarction (MI), coronary artery disease and heart failure (HF). Males also had lower EF and HDL cholesterol and higher LA volume and LV mass, serum glucose, insulin and diastolic pressure. The presence of the rs5068 minor allele improved the cardiometabolic phenotype including BP and widespread metabolic parameters in males but not females. After adjustment by age, males had increased risk of all-cause mortality, HF, MI, and stroke. Conclusions: Males are characterized by a relative ANP deficiency compared to females and widespread prevalence of cardiometabolic disease and increased CV morbidity and mortality in the general population. We demonstrate that the cardiometabolic protective action of the ANP gene variant rs5068 minor allele is sex dependent and protective in males. These findings have diagnostic and therapeutic implications, particularly in males.

Modification of Serum Natriuretic Peptide Profile and Echocardiographic Parameters After Surgical Left Atrial Appendage Exclusion/Resection During Mitral Valve Surgery

Being a well-recognised source of cardiac embolism, the left atrial (LA) appendage (LAA) is frequently excluded during mitral valve (MV) surgery. However, the LAA is also a source of cardiac hormones and a new drug (sacubitril), which beneficially interferes with hormonal imbalance during heart failure, leads to re-evaluation of the LAA for the maintenance of adequate hormone production in the heart. We compared the effects of LAA surgical resection/exclusion in patients with MV replacement (MVR) on natriuretic peptides (NPs) and related enzymes versus similar patients, in whom the LAA was preserved. A comparison of clinical response was also carried out. Haemodynamically stable patients scheduled for MV surgery with or without elimination of the LAA were studied before and 3 months after surgery. Serum NPs, furin, corin, and neprilysin were determined. A transthoracic echocardiogram was also performed before and after surgery. Patients in the LAA intervention group exhibited lower levels of atrial natriuretic peptide (ANP) 3 months after surgery than patients with intact LAAs. There were no differences in NP and related enzyme levels pre- or postsurgery. The echocardiograms indicated a similar decrease in the diameters and volumes of the LA, and normal pulmonary arterial pressure values, in both groups. The indexed LA volume showed a positive correlation with postoperative brain natriuretic peptide. Surgical resection or exclusion of the LAA in patients with MVR promotes a decrease in ANP production at 3 months postsurgery. Echocardiography is useful when evaluating surgical replacement of the MV with elimination of the LAA.

Cardiac Autophagy Deficiency Attenuates ANP Production and Disrupts Myocardial-Adipose Cross Talk, Leading to Increased Fat Accumulation and Metabolic Dysfunction.

Increased myocardial autophagy has been established as an important stress-induced cardioprotective response. Three weeks after generating cardiomyocyte-specific autophagy deficiency, via inducible deletion of autophagy-related protein 7 (Atg7), we found that these mice (AKO) had increased body weight and fat mass without altered food intake. Glucose and insulin tolerance tests indicated reduced insulin sensitivity in AKO mice. Metabolic cage analysis showed reduced ambulatory activity and oxygen consumption with a trend of elevated respiratory exchange ratio in AKO mice. Direct analysis of metabolism in subcutaneous and visceral adipocytes showed increased glucose oxidation and reduced ATGL expression and HSL phosphorylation with no change in lipid synthesis or fatty acid oxidation. Importantly, we found AKO mice had reduced myocardial and circulating levels of atrial natriuretic peptide (ANP), an established mediator of myocardial-adipose cross talk. When normal ANP levels were restored to AKO mice with use of osmotic pump, the metabolic dysfunction evident in AKO mice was corrected. We conclude that cardiac autophagy deficiency alters myocardial-adipose cross talk via decreased ANP levels with adverse metabolic consequences.

Anp Production Is Impaired in Acute Decompensated Heart Failure

Atrial natriuretic peptide (ANP) is secreted under myocardial stress in heart failure (HF) as a compensatory mechanism sustaining cardiorenal homeostasis. Recent studies have underscored the importance of ANP in HF as with sacubitril/valsartan administration, ANP is markedly increased in the absence of an increase in BNP, supportive of ANP's cardiorenal enhancing properties. However, the presence of an ANP deficiency in HF may attenuate ANP's beneficial actions in HF. As ANP is highly susceptible to degradation by neprilysin, characterizing ANP levels within the circulation becomes difficult when assessing whether production or degradation may confer this deficiency state. By using ANP's biologically inactive equivalent, NTproANP, which is highly resistant to degradation, one may quantify production/secretion of the ANP system to assess the overall biological activity of ANP. Therefore, we sought to characterize NTproANP in human acute decompensated HF (ADHF) to elucidate this potential ANP deficiency state and to provide details into its regulation in ADHF. We prospectively recruited 47 healthy individuals without cardiovascular or metabolic disease to determine NTproANP in healthy subjects. A contemporary NTproANP cutoff was then created by using the 95th percentile NTproANP value within this healthy cohort, to distinguish amongst our 107 prospectively recruited ADHF patients whom had either NTproANP values below the NTproANP cutoff, deemed NTproANP Deficient, or above the cutoff, deemed having an Elevated NTproANP. Clinical biomarkers between subgroups were then compared to determine whether differences persisted based upon NTproANP levels. In ADHF, 20% of patients were NTproANP Deficient whereas 80% had an Elevated NTproANP . The NTproANP Deficient cohort demonstrated lower median NTproANP (116.1 vs. 708.6 pg/mL, p

Novel Antihypertension Mechanism of β-Glucan by Corin and ANP-Mediated Natriuresis in Mice

Many of the β-glucans are known to have antihypertensive activities, but, except for angiotensin-converting enzyme II inhibition, the underlying mechanisms remain unclear. Corin is an atrial natriuretic peptide (ANP)-converting enzyme. Activated corin cleaves pro-ANP to ANP, which regulates water–sodium balance and lowers blood pressure. Here, we reported a novel antihypertensive mechanism of β-glucans, involved with corin and ANP in mice. We showed that multiple oral administrations of β-glucan induced the expression of corin and ANP, and also increased natriuresis in mice. Microarray analysis showed that corin gene expression was only upregulated in mice liver by multiple, not single, oral administrations of the β-glucan fraction of Phellinus baumii (BGF). Corin was induced in liver and kidney tissues by the β-glucans from zymosan and barley, as well as by BGF. In addition to P. baumii, β-glucans from two other mushrooms, Phellinus linteus and Ganoderma lucidum, also induced corin mRNA expression in mouse liver. ELISA immunoassays showed that ANP production was increased in liver tissue by all the β-glucans tested, but not in the heart and kidney. Urinary sodium excretion was significantly increased by treatment with β-glucans in the order of BGF, zymosan, and barley, both in 1% normal and 10% high-sodium diets. In conclusion, we found that the oral administration of β-glucans could induce corin expression, ANP production, and sodium excretion in mice. Our findings will be helpful for investigations of β-glucans in corin and ANP-related fields, including blood pressure, salt–water balance, and circulation.

The relation and mechanism of kidney injury in obstructive sleep apnea: a literature review

Up to date, it is found that the presence of obstructive sleep apnea (OSA) contributes to the development of structural, ultra-structural, functional, and proteomics changes in the kidney. These changes are based on pathological processes, such as increased production of free radicals, disruption of mediated NO vasodilation reactions, activation of the sympathetic autonomic nervous system, the renin–angiotensin–aldosterone system, dysfunction of endothelium, the development of renal venous hypertension, and stimulation of atrial natriuretic peptide production. All this in turn contributes to an increase in intra-glomerular pressure, the occurrence of glomerular hyperfiltration, nocturnal polyuria, renal functional changes, proteinuria and renal tubular dysfunction. Kidney injury in OSA patients can also be caused by pathological conditions associated with OSA, such as cor pulmonale, erythrocytosis, diabetes mellitus, metabolic syndrome, hypertension, coronary heart diseases, and atherosclerosis, which in isolated conditions can lead to development of kidney damage, and co-occurring with OSA can even aggravate the course of the latter. There is a bidirectional relationship between kidney diseases and OSA through a number of potential pathological mechanisms, which suggests the possibility of both diseases to be a possible risk factor for each other. Moreover, kidney diseases may lead to OSA through a multifarious of mechanisms, including chemoreflex responsiveness, pharyngeal narrowing due to fluid overload, and accumulation of uremic toxins.

SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES

SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES

CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.

SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production.

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.

Acute Metabolic Influences on the Natriuretic Peptide System in Humans

BackgroundThe cardiac natriuretic peptides (NPs), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), have central roles in sodium and blood pressure regulation. Extracardiac factors (e.g., obesity and diabetes) influence NP production, potentially altering cardiovascular responses to volume and pressure stress. ObjectivesThis study examined the effects of acute carbohydrate intake on the NP system in humans, and investigated underlying mechanisms. MethodsNormotensive subjects (N = 33) were given a high-carbohydrate shake. Venous blood was sampled to measure N-terminal (NT)-proANP and NT-proBNP levels. Human embryonic stem cell–derived cardiomyocytes (hESC-CMs) and HepG2 cells were treated with glucose, and expression levels of NPs and micro ribonucleic acid 425 (miR-425), a negative regulator of ANP, were examined. The role of nuclear factor kappa B (NF-κB) in the glucose-mediated effects was investigated using a NF-κB inhibitor and expression plasmids encoding NF-κB subunits. ResultsWe observed a 27% reduction in the levels of circulating NT-proANP (p < 0.001, maximal at 6 h) after carbohydrate challenge, with no effect on NT-proBNP levels in our human subjects. Glucose treatment of hESC-CMs for 6 h and 24 h increased levels of the primary transcript of miR-425 (pri-miR-425) and mature miR-425. A corresponding decrease in NPPA messenger RNA levels was also observed at both time points. Overexpression of NF-κB subunits in H9c2 cardiomyocytes increased miR-425 levels, whereas inhibition of NF-κB abrogated the glucose-mediated increase in pri-miR-425 levels in HepG2 cells. ConclusionsAcute carbohydrate challenge is associated with a reduction in ANP production. The mechanism appears to involve a glucose-induced increase in the expression of miR-425, mediated by NF-κB signaling.

Case Report: Hyponatremia of malignancy – An alternative mechanism? Syndrome of inappropriate atrial natriuretic peptide (SIANP)

Euvolemic hyponatremia in the setting of lung cancer is most commonly due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, a subset of patients with small cell carcinoma and hyponatremia also have elevated levels of atrial natriuretic peptide (ANP), which is produced by some small cell tumors. We report the case of a 64-year-old man with a limited-stage small cell carcinoma of the lung undergoing chemoradiation therapy, who was admitted to hospital with a pulmonary embolism. Two months earlier, at the time of diagnosis with lung cancer, he had a hypotonic, euvolemic hyponatremia, presumed to be caused by SIADH. At that time, his serum sodium readily normalized with fluid restriction and ADH-antagonist therapy with demeclocycline. However, during his second admission, the hyponatremia was refractory to treatment: his sodium level slowly declined from 138 mmol/L to a nadir of 118 mmol/L, despite early initiation of fluid restriction and maximal doses of demeclocycline. Laboratory values revealed a low but inappropriately non-zero level of ADH but also an inappropriately low level of aldosterone and an elevated level of ANP, suggesting that SIADH might not be the only contributor to the hyponatremia. While a causal link between ectopic ANP production and hyponatremia has never been established, an inappropriately high level of ANP can directly decrease sodium re-absorption in the proximal convoluted tubule of the kidney and increase glomerular filtration rate (GFR), resulting in greater excretion of sodium and water. In addition, high circulating levels of ANP can inhibit aldosterone secretion, potentially resulting in further sodium wasting. Here, the elevated ANP and inappropriately low aldosterone suggested the possibility that the refractory hyponatremia, although initiated by SIADH, was further worsened by an ANP-mediated natriuresis and suppression of aldosterone response.

Case Report: Hyponatremia of malignancy – An alternative mechanism? Syndrome of inappropriate atrial natriuretic peptide (SIANP)

Euvolemic hyponatremia in the setting of lung cancer is most commonly due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, some patients with small cell carcinoma and hyponatremia have low levels of ADH but elevated levels of atrial natriuretic peptide (ANP), which is produced by some small cell tumors. We report the case of a 64-year-old man with a limited-stage small cell carcinoma of the lung undergoing chemoradiation therapy, who was admitted to hospital with a pulmonary embolism. Two months earlier, at the time of diagnosis with lung cancer, he had a hypotonic, euvolemic hyponatremia, presumed to be caused by SIADH. At that time, his serum sodium readily normalized with water restriction and ADH-antagonist therapy with demeclocycline. However, during his second admission, his sodium level slowly declined from 138 mmol/L to a nadir of 118 mmol/L, despite early initiation of water restriction and maximal doses of demeclocycline. Laboratory values revealed a very low level of ADH, an inappropriately low level of aldosterone and an elevated ANP suggesting that SIADH could not explain his hyponatremia. While a causal link between ectopic ANP production and hyponatremia has never been established, an inappropriately high level of ANP can directly decrease sodium re-absorption in the proximal convoluted tubule of the kidney and increase glomerular filtration rate (GFR), resulting in greater excretion of sodium and water. In addition, high circulating levels of ANP can inhibit aldosterone secretion, potentially resulting in further sodium wasting. Here, the low levels of ADH, elevated ANP, and inappropriately low aldosterone suggested the possibility of an ANP-mediated hyponatremia through the suppression of aldosterone response.

RNA Sequencing Analysis and Atrial Natriuretic Peptide Production in Patients with Dilated and Ischemic Cardiomyopathy

BackgroundThe atrium is the major site of ANP synthesis, which has been said to increase in heart failure as a result of increased production in the left ventricular (LV) myocardium. This is a key issue related to its diagnostic and prognostic capabilities. We aimed to evaluate protein levels of proANP and ANP and the enzymes that cleave the natriuretic peptides, corin and furin, in the LV tissue of heart transplant patients with dilated (DCM) and ischemic (ICM) cardiomyopathy compared with control donors (CNT). We also evaluate mRNA levels of ANP gene (NPPA) by RNA sequencing in the same tissue.Methods and ResultsSeventy-three human LV tissue samples from ICM (n = 30) and DCM (n = 33) patients and CNT (n = 10) were analyzed by Western blot and RNA sequencing. Comparing protein levels according to etiology, neither DCM nor ICM showed levels of proANP or ANP different from those of CNT. However, NPPA was increased in both groups compared to CNT (DCM 32 fold, p<0.0001; ICM 10 fold, p<0.0001). Corin (but not furin) was elevated in the ICM group compared to CNT (112±24 vs. 100±7, p<0.05), and its level was inversely related with LV ejection fraction (LVEF) (r = −0.399, p<0.05).ConclusionsPatients present with elevated levels of NPPA but not of proANP or ANP proteins in LV tissue, which may be due to posttranscripcional regulation of NPPA or different pathways for ANP secretion between the atrium and ventricle. Moreover, there are differences between DCM and ICM in corin levels, indicating that a different molecular mechanism may exist that converge in this syndrome. Further, LV concentration of corin is inversely related to LVEF in ICM.

Low Plasma Atrial Natriuretic Peptide: A New Piece in the Puzzle of Polycystic Ovary Syndrome

It is believed that a dysfunction in adipose tissue plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Natriuretic peptides are hormones that regulate cardiovascular and body fluid homeostasis and adipose tissue metabolism. Natriuretic peptide levels are reduced in individuals with obesity and diabetes. This study aimed to investigate whether natriuretic peptide levels are altered in women with PCOS and whether they correlate with adiponectin levels or insulin sensitivity markers. This was a cross-sectional study at a referral center in a teaching hospital. We evaluated 40 patients diagnosed with PCOS according to the Rotterdam criteria and 36 control women matched for age and body mass index. We measured serum adiponectin, plasma atrial natriuretic peptide (ANP), and plasma brain natriuretic peptide using enzyme immunoassays in both groups. We evaluated metabolic markers, such as fasting glucose, insulin, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. In addition, we calculated the homeostasis model assessment for insulin resistance index (HOMA-IR) and the lipid accumulation product (LAP) index and tested the linear correlations between these metabolic indices and the plasma ANP and serum adiponectin concentrations. ANP and adiponectin were reduced in the PCOS group compared with the control group (P = 0.010 and P = 0.014, respectively). The brain natriuretic peptide concentration did not differ between the two groups (P = 0.883). There was no correlation between ANP and any of the metabolic markers. In the control group, the serum adiponectin level was inversely correlated with BMI (P = 0.011), waist circumference (P = 0.021), insulin (P = 0.013), fasting glucose (P = 0.010), homeostasis model assessment for insulin resistance index (P = 0.007), and lipid accumulation product (P = 0.022). Remarkably, none of these correlations were observed in the women with PCOS. Women with PCOS had lower ANP and adiponectin compared with controls matched for age and BMI. Thus, the mechanisms that affect ANP and adiponectin production and clearance may be altered in PCOS, regardless of adiposity. These hormones may be involved in the metabolic features of PCOS.

Atrial natriuretic peptide is negatively regulated by microRNA-425

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.