ANP (Atrial Natriuretic Peptide) Research & Studies

Disturbance in protein synthesis and degradation plays a crucial role in various biological and pathological processes. E3 ubiquitin ligase substrate-binding adaptor SPOP (speckle-type POZ [poxvirus and zinc finger] protein) is substantially involved in cancer progression. The study aims to investigate the biological function of SPOP in cardiac hypertrophy and heart failure.

Pathological cardiac remodeling is a critical process leading to heart failure, characterized primarily by inflammation and apoptosis. Matairesinol (Mat), a key chemical component of Podocarpus macrophyllus resin, exhibits a wide range of pharmacological activities, including anti-hydatid, antioxidant, antitumor, and anti-inflammatory effects.

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection. Since neither the NP-mediated renal functions nor the renal target cells of renoprotection are completely understood, we performed systematic localization studies of NP receptors using in situ hybridization (RNAscope) in mouse kidneys. NPR-A mRNA is highly expressed in glomeruli (mainly podocytes), renal arterioles, endothelial cells of peritubular capillaries, and PDGFR-receptor β positive (PDGFR-β) interstitial cells. No NPR-A mRNA was detected by RNAscope in the tubular system. In contrast, NPR-B expression is highest in proximal tubules. NPR-C is located in glomeruli (mainly podocytes), in endothelial cells and PDGFR-β positive cells. To test for a possible regulation of NPRs in kidney diseases, their distribution was studied in adenine nephropathy. Signal intensity of NPR-A and NPR-B mRNA was reduced while their spatial distribution was unaltered compared with healthy kidneys. In contrast, NPR-C mRNA signal was markedly enhanced in cell clusters of myofibroblasts in fibrotic areas of adenine kidneys. In conclusion, the primary renal targets of ANP and BNP are glomerular, vascular, and interstitial cells but not the tubular compartment, while the CNP receptor NPR-B is highly expressed in proximal tubules. Further studies are needed to clarify the function and interplay of this specific receptor expression pattern.

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF.

Whether systolic blood pressure (SBP) control in sustained volume-dependent primary hypertension is associated with blunted ANP (atrial natriuretic peptide) relationships with indexes of volume load is unknown.

Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes.

With aging, the human atrium invariably develops amyloid composed of ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide). Preamyloid oligomers are the primary cytotoxic species in amyloidosis, and they accumulate in the atrium during human hypertension and a murine hypertensive model of atrial fibrillation susceptibility. We tested the hypothesis that preamyloid oligomers derived from natriuretic peptides cause cytotoxic and electrophysiological effects in atrial cells that promote arrhythmia susceptibility and that oligomer formation is enhanced for a mutant form of ANP linked to familial atrial fibrillation.

ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP.

The glycocalyx is a ubiquitous structure found on endothelial cells that extends into the vascular lumen. It is enriched in proteoglycans, which are proteins attached to the glycosaminoglycans heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid. In health and disease, the endothelial glycocalyx is a central regulator of vascular permeability, inflammation, coagulation, and circulatory tonicity. During sepsis, a life-threatening syndrome seen commonly in hospitalized patients, the endothelial glycocalyx is degraded, significantly contributing to its many clinical manifestations. In this review we discuss the intrinsically linked mechanisms responsible for septic endothelial glycocalyx destruction: glycosaminoglycan degradation and proteoglycan cleavage. We then examine the consequences of local endothelial glycocalyx loss to several organ systems and the systemic consequences of shed glycocalyx constituents. Last, we explore clinically relevant non-modifiable and modifiable factors that exacerbate or protect against endothelial glycocalyx shedding during sepsis.

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

The heart plays a central role in the circulatory system and provides essential oxygen, nutrients, and growth factors to the whole organism. The heart can synthesize and secrete endocrine signals to communicate with distant target organs. Studies of long-known and recently discovered heart-derived hormones highlight a shared theme and reveal a unified mechanism of heart-derived hormones in coordinating cardiac function and target organ biology. This paper reviews the biochemistry, signaling, function, regulation, and clinical significance of representative heart-derived hormones, with a focus on the cardiovascular system. This review also discusses important and exciting questions that will advance the field of cardiac endocrinology.

Cardiac ANP (atrial natriuretic peptide) moderates arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve inhibition of the renin-angiotensin-aldosterone system, increased natriuresis, endothelial permeability, and vasodilatation. The contribution of the direct vasodilating effects of ANP to blood pressure homeostasis is controversial because variable levels of the ANP receptor, GC-A (guanylyl cyclase-A), are expressed among vascular beds. Here, we show that ANP stimulates GC-A/cyclic GMP signaling in cultured microvascular pericytes and thereby the phosphorylation of the regulatory subunit of myosin phosphatase 1 by cGMP-dependent protein kinase I. Moreover, ANP prevents the calcium and contractile responses of pericytes to endothelin-1 as well as microvascular constrictions. In mice with conditional inactivation (knock-out) of GC-A in microcirculatory pericytes, such vasodilating effects of ANP on precapillary arterioles and capillaries were fully abolished. Concordantly, these mice have increased blood pressure despite preserved renal excretory function. Furthermore, acute intravascular volume expansion, which caused release of cardiac ANP, did not affect blood pressure of control mice but provoked hypertensive reactions in pericyte GC-A knock-out littermates. We conclude that GC-A/cGMP-dependent modulation of pericytes and microcirculatory tone contributes to the acute and chronic moderation of arterial blood pressure by ANP. Graphic Abstract A graphic abstract is available for this article.

Although there is a substantial amount of research on the neurological consequences of traumatic brain injury (TBI), there is a knowledge gap regarding the relationship between TBI and the pathophysiology of organ system dysfunction and autonomic dysregulation. In particular, the mechanisms or incidences of renal or cardiac complications after TBI are mostly unknown. Autonomic dysfunction following TBI exacerbates secondary injury and may contribute to nonneurologial complications that prolong hospital length of stay. Gaining insights into the mechanisms of autonomic dysfunction can guide advancements in monitoring and treatment paradigms to improve acute survival and long-term prognosis of TBI patients. In this paper, the authors will review the literature on autonomic dysfunction after TBI and possible mechanisms of paroxysmal sympathetic hyperactivity. Specifically, they will discuss the link among the brain, heart, and kidneys and review data to direct future research on and interventions for TBI-induced autonomic dysfunction.

There has been a large confirmation over the last decades that stroke may produce cardiac changes (echocardiographic, electrocardiographic, enzymatic). In ischemic stroke, systolic dysfunction is associated with a high risk of mortality during hospitalization. A recent study demonstrated that cardiac diastolic dysfunction could also accompany acute stroke besides the systolic dysfunction already pointed out by previous studies, being a predictive marker of acute cerebrovascular events. Increased sympathetic activity is contributory, inducing a reversible cardiac myocyte damage and cardiac enzyme surges. Some of the most frequent electrocardiographic abnormalities in stroke are ST segment abnormalities and various tachyarrhythmias (especially atrial fibrillation) and bradyarrhythmias. One can infer the importance of careful and continuous electrocardiographic monitoring of the stroke patient in order to identify these quite frequent electrocardiographic alterations, as it is well known that death due to cardiac arrhythmias is common among acute stroke patients. In order to increase the diagnostic yield, a high level of NTproBNP (N-terminal of the prohormone brain natriuretic peptide) may be used as a discriminant for the patients with a higher probability of cardiac arrhythmias and mortality at presentation, during hospitalization and on the long term. In such patients, cardiac monitoring techniques are more likely to reveal abnormalities. A high BNP level may have potentially important management implications as it may signal a worse prognosis and may prompt the undertaking of certain therapeutic measures. This review summarizes the possible pathological mechanisms of heart-brain connections and their clinical and therapeutical implications.

ANP (atrial natriuretic peptide), discovered 30 years ago in rat cardiac atria, has been extensively investigated with regard to physiology, pathophysiology, cardiovascular disease therapeutics and molecular genetic aspects. Besides its diuretic, natriuretic and vasorelaxant effects, novel properties of this hormone have been described. Thus anti-hypertrophic, anti-fibrotic, anti-proliferative and anti-inflammatory actions suggest that ANP contributes not only to haemodynamic homoeostasis and adjustments, but has also a role in cardiovascular remodelling. Circulating ANP levels represent a valuable biomarker in cardiovascular diseases. ANP structure is highly conserved among species, indicating a key role in cardiovascular health. Thus an abnormal ANP structure may contribute to an increased risk of disease due to altered functions at either the vascular or cardiac level. Among others, the 2238T>C exon 3 variant has been associated with endothelial cell damage and dysfunction and with an increased risk of acute cardiovascular events, a frameshift mutation within exon 3 has been related to increased risk of atrial fibrillation, and ANP gene variants have been linked to increased risk of hypertension in different ethnic groups. On the other hand, the rs5068 variant, falling within the 3' UTR and associated with higher circulating ANP levels, has been shown to have a beneficial cardioprotective and metabolic effect. Dissecting out the disease mechanisms dependent on specific ANP molecular variants may reveal information useful in the clinical setting for diagnostic, prognostic and therapeutic purposes. Furthermore, insights from molecular genetic analysis of ANP may well integrate advancing knowledge on the role of ANP as a significant biomarker in patients affected by cardiovascular diseases.

Recent studies suggest that the ANP (atrial natriuretic peptide)/NPRA (type A natriuretic peptide receptor) system modulates ventricular remodelling and cardiac hypertrophy in hypertension in Western populations. In the present study, we tested for any association between two SNPs (single nucleotide polymorphisms) in the ANP gene (one in the promoter and one exonic) with cardiac hypertrophy. We tested the hypothesis in 2118 hypertensive patients, including 945 with LVH [LV (left ventricular) hypertrophy] and 1173 without LVH, as well as 816 healthy control subjects. All subjects were genotyped for the -A2843G and A188G polymorphisms. We found that the GG genotype at position -2843 conferred a 2.2-fold risk for LVH compared with the AA or AG genotypes, including septal wall thickness (11.8+/-1.4 mm for GG compared with 10.9+/-1.4 and 10.7+/-1.3 mm for AA and AG respectively; P<0.01), posterior wall thickness (11.8+/-2.8 mm for GG compared with 10.6+/-1.2 and 10.6+/-1.4 mm for AA and AG respectively; P<0.01), LV mass index (62.7+/-13.6 g/m(2.7) for GG compared with 57.9+/-8.6 and 57.8+/-8.4 g/m(2.7) for AA and AG respectively; P<0.05) and relative wall thickness (50.7+/-10.8% for GG compared with 44.3+/-7.3 and 43.5+/-6.8% for AA and AG respectively; P<0.05). Plasma levels of ANP were significantly lower in the hypertensive patients with LVH carrying the GG genotypes compared with those carrying the AA or AG genotypes (P<0.01). No association of GG genotype with echocardiographic variables and plasma ANP levels was identified in hypertensive patients without LVH and in control subjects (P>0.05). No significant association between the A188G genotype and echocardiographic variables was found in either hypertensive patients or controls (P>0.05). In conclusion, our findings indicate that the -A2843G polymorphism in the ANP gene promoter might be a genetic risk factor for the development of LVH in patients with hypertension.

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.

Atrial natriuretic peptide (ANP) was measured in plasma during acute volume load in conscious, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. During basal conditions immunoreactive ANP were similar in the SHR (630 +/- 56 pmoles l-1) and the WKY (657 +/- 114 pmoles l-1) groups. An acute 10% and 20% whole blood volume expansion resulted in a linear increase in immunoreactive plasma ANP in the WKY. In the SHR the increase in plasma ANP was attenuated during the 20% volume load. During the 10% and 20% volume load central venous pressure (CVP), central blood volume (CBV) and cardiac output increased relatively more in the SHR compared with the WKY group. In contrast, the increase in peripheral blood volume (PBV) and decrease in heart rate (HR) was attenuated in the SH rats. In the SHR group there was a shift of the ANP vs. CVP and ANP vs. CBV curves to the right compared with the WKY. We conclude that acute volume loading is a potent stimulus for ANP release in WKY as well as SHR. However, in the SHR, ANP release was blunted in spite of the increased centralization of the volume load in this rat strain. Thus, the decreased responsiveness of the ANP hormonal system may contribute to the development and maintenance of hypertension in this genetic form of hypertension.