Atrial natriuretic peptide

NPPA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1ANP, 1YK0, 3N57
Identifiers
Aliases	NPPA, ANF, ANP, ATFB6, ATRST2, CDD, CDD-ANF, CDP, PND, Atrial natriuretic peptide, natriuretic peptide A
External IDs	OMIM: 108780 MGI: 97367 HomoloGene: 4498 GeneCards: NPPA
Gene ontology Molecular function • neuropeptide receptor binding • hormone activity • peptide hormone receptor binding • neuropeptide hormone activity • protein binding • receptor binding Cellular component • cytoplasm • mast cell granule • Q40260 • perinuclear region of cytoplasm • extracellular region • extracellular space • protein complex Biological process • response to muscle stretch • positive regulation of cardiac muscle contraction • response to hypoxia • regulation of high voltage-gated calcium channel activity • neuropeptide signaling pathway • female pregnancy • regulation of cardiac conduction • negative regulation of collecting lymphatic vessel constriction • positive regulation of potassium ion export across plasma membrane • cellular protein metabolic process • regulation of blood vessel size • positive regulation of heart rate • positive regulation of delayed rectifier potassium channel activity • cGMP biosynthetic process • regulation of blood pressure • negative regulation of systemic arterial blood pressure • regulation of calcium ion transmembrane transport via high voltage-gated calcium channel • transcription initiation from RNA polymerase II promoter • regulation of atrial cardiac muscle cell membrane repolarization • response to insulin • cell growth involved in cardiac muscle cell development • negative regulation of cell growth • cardiac muscle hypertrophy in response to stress • cellular response to mechanical stimulus • receptor guanylyl cyclase signaling pathway • protein folding Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4878	230899
Ensembl	ENSG00000175206	ENSMUSG00000041616
UniProt	P01160	P05125
RefSeq (mRNA)	NM_006172	NM_008725
RefSeq (protein)	NP_006163	NP_032751
Location (UCSC)	Chr 1: 11.85 – 11.85 Mb	Chr 4: 148 – 148 Mb
PubMed search	[1]	[2]
Wikidata
View/Edit Human View/Edit Mouse

Atrial natriuretic peptide (ANP), also called atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), cardionatrine, cardiodilatin (CDD), or atriopeptin, is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells.^[3][4][5] It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue). It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes) in response to high blood volume. ANP acts to reduce the water, sodium, and adipose loads on the circulatory system, thereby reducing blood pressure.^[3] ANP has exactly the opposite function of the aldosterone secreted by the zona glomerulosa in regard to its effect on sodium in the kidney – that is, aldosterone stimulates sodium retention and ANP generates sodium loss.^[6][7]

Discovery

ANP was discovered in the early 1980s. de Bold and colleagues in Kingston, Ontario, Canada found that rat atrial extracts contained a substance that increased salt and urine output in the kidney.^[8] Later, the substance was purified from the heart by several groups and named ANF or ANP.^[9]

Structure

ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23. ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share a similar amino acid ring structure.

Production

Human ANP is encoded by the NPPA gene on the short arm of chromosome 1, which has 3 exons and 2 introns. The gene is expressed primarily in cardiac myocytes. Lower levels of NPPA expression are found in other tissues such as the brain, kidney, lung, uterus and placenta.

In cardiac myocytes, ANP is made as a precursor form, i.e. prepro-ANP, a polypeptide of 151 amino acids. After the signal peptide is removed in the endoplasmic reticulum, the 126-amino-acid pro-ANP is stored in the intracellular granules. When the cells are stimulated, pro-ANP is released and converted to the 28-amino-acid C-terminal mature ANP on the cell surface by the cardiac transmembrane serine protease corin.^[10][11]

ANP is secreted in response to:

• Stretching of the atrial wall^[3]
• Increased Sympathetic stimulation of β-adrenoceptors
• Raised sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion^[3]
• Endothelin, a potent vasoconstrictor
• Exercise^[12]

Receptors

Three types of atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. They are all cell surface receptors and designated:

• guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANP_A) or NPR1
• guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANP_B) or NPR2
• natriuretic peptide clearance receptor (NPRC/ANP_C) or NPR3

NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds the ligand. The intracellular domain maintains two consensus catalytic domains for guanylyl cyclase activity. Binding of a natriuretic peptide induces a conformational change in the receptor that causes receptor dimerization and activation.

The binding of ANP to its receptor causes the conversion of GTP to cGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) that phosphorylates proteins at specific serine and threonine residues. In the medullary collecting duct, the cGMP generated in response to ANP may act not only through PKG but also via direct modulation of ion channels.^[13]

NPR-C functions mainly as a clearance receptor by binding and sequestering ANP from the circulation. All natriuretic peptides are bound by the NPR-C.

ANP and brain natriuretic peptide bind and activate GC-A, whereas CNP binds and activates GC-B.^[14]

Physiological effects

ANP binds to a specific set of receptors – ANP receptors. Receptor-agonist binding causes a reduction in blood volume and, therefore, a reduction in cardiac output and systemic blood pressure. Lipolysis is increased and renal sodium reabsorption is decreased. The overall effect of ANP on the body is to counter increases in blood pressure and volume caused by the renin-angiotensin system.

Renal

• Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the glomerular filtration rate (GFR), resulting in greater filter load of sodium and water.
• Increases blood flow through the vasa recta, which will wash the solutes (NaCl and urea) out of the medullary interstitium.^[15] The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
• Decreases sodium reabsorption in the distal convoluted tubule (interaction with NCC)^[16] and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC.
• Its natriuretic effect is affected by dopamine and dopamine receptor D₁ activity in vivo ^[17]
• Inhibits renin secretion, thereby inhibiting the renin–angiotensin–aldosterone system.

Adrenal

• Reduces aldosterone secretion by the zona glomerulosa of the adrenal cortex.

Vascular

Relaxes vascular smooth muscle in arterioles and venules by:

• Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
• Inhibition of the effects of catecholamines

Promotes uterine spiral artery remodeling, which is important for preventing pregnancy-induced hypertension.^[18]

Cardiac

• Inhibits maladaptive cardiac hypertrophy
• Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly^[19]
• Re-expression of NPRA rescues the phenotype.

It may be associated with isolated atrial amyloidosis.^[20]

Adipose tissue

• Increases the release of free fatty acids from adipose tissue. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
• Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A
• Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a cGMP-dependent protein kinase-I (cGK-I)
• Does not modulate cAMP production or PKA activity

Degradation

Regulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzyme neutral endopeptidase (NEP). Recently, NEP inhibitors have been developed; however they have not yet been licensed. They may be clinically useful in treating congestive heart disease.

Biomarker

Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.^[21] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.^{[22][23][24][25]}

Large amounts of ANP secretion has been noted to cause electrolyte disturbances (hyponatremia) and polyuria. These indications can be a marker of a large atrial myxoma.^[26]

Therapeutic use and drug development

Recombinant human ANP has been approved in Japan to treat patients with heart failure.^[27]

As of 2017 a truncated form of ANP called ularitide was under development in Phase III trials for heart failure.^[28]

Other natriuretic factors

In addition to the mammalian natriuretic peptides (ANP, BNP, CNP), other natriuretic peptides with similar structure and properties have been isolated elsewhere in the animal kingdom. Tervonen (1998) described a salmon natriuretic peptide known as salmon cardiac peptide,^[29] while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.^[30]

Pharmacological modulation

Neutral endopeptidase (NEP) also known as neprilysin is the enzyme that metabolizes natriuretic peptides. Several inhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure. Most of them are dual inhibitors (NEP and ACE). In 2014, PARADIGM-HF study was published in NEJM. This study considered as a landmark study in treatment of heart failure. The study was double blinded; compared LCZ696 versus enalapril in patients with heart failure. The study showed lower all cause mortality, cardiovascular mortality and hospitalization in LCZ696 arm.^[31] Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.^[32]

See also

• Atrial volume receptors
• Brain natriuretic peptide
• C-type natriuretic peptide

References

External links

• Atrial Natriuretic Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human NPPA genome location and NPPA gene details page in the UCSC Genome Browser.