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Review Article NATRIURETIC PEPTIDES in CARDIOVASCULAR CELLULAR & MOLECULAR BIOLOGY LETTERS http://www.cmbl.org.pl Received: 18 January 2007 Volume 13 (2008) pp 155-181 Revised form accepted: 08 May 2007 DOI: 10.2478/s11658-007-0046-6 Published online: 29 October 2007 © 2007 by the University of Wrocław, Poland Review article NATRIURETIC PEPTIDES IN CARDIOVASCULAR DISEASES MARIUSZ PIECHOTA1, MACIEJ BANACH2*, ANNA JACOŃ3 and JACEK RYSZ4 1Department of Anaesthesiology and Intensive Care Unit, Boleslaw Szarecki University Hospital No. 5 in Łódź, Medical University in Łódź, Poland, 2Department Cardiology, 1st Chair of Cardiology and Cardiac Surgery, University Hospital No. 3 in Łódź, Medical University in Łódź, Poland, 3Department of Health Protection Policy, Medical University of Łódź, Poland 42nd Department of Family Medicine, University Hospital No. 2 in Łódź, Medical University in Łódź, Poland Abstract: The natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. The activities of natriuretic peptides and endothelins are strictly associated with each other. ANP and BNP inhibit endothelin-1 (ET-1) production. ET-1 stimulates natriuretic peptide synthesis. All natriuretic peptides are synthesized from polypeptide precursors. Changes in natriuretic peptides and endothelin release were observed in many cardiovascular diseases: e.g. chronic heart failure, left ventricular dysfunction and coronary artery disease. Key words: Atrial natriuretic peptide, Brain natriuretic peptide, C-type natriuretic peptide, Dendroaspis natriuretic peptide, Urodilatin, Endothelin-1 * Author for correspondence: Department of Cardiology, Medical University of Łódź, Sterlinga 1/3, 91-425 Łódź, Poland, tel/fax: +48 42 6364 471, e-mail: [email protected] Abbreviations used: ACTH – adrenocorticotropic hormone; ANP – atrial natriuretic peptide; AVP – arginine vasopressin; BNP – brain natriuretic peptide; CHF – chronic heart failure; CNP – C-type natriuretic peptide; cGMP – cyclic guanosine monophosphate; DNP – dendroaspis natriuretic peptide; ET – endothelin; FGF – fibroblast growth factor; NO – nitric oxide; NYHA – New York Heart Association; PAI – plasminogen activator inhibitor; PGDF – platelet derived growth factor; TGF – transforming growth factor; TIMP – tissue inhibitor of matrix metalloproteinase; TNF – tumor necrosis factor 156 Vol. 13. No. 2. 2008 CELL. MOL. BIOL. LETT. INTRODUCTION The natriuretic peptide family comprises atrial natriuretic peptide (ANP; A-type natriuretic peptide), brain natriuretic peptide (BNP; B-type natriuretic peptide), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. Atrial natriuretic peptide was the first to be identified, in 1981 [1]. In 1984, Kangawa and Matsuo published the full amino acid sequence of human ANP [2]. ANP is a peptide made up of 28 amino acids, and it is first secreted by the heart atria. Brain natriuretic peptide was identified in 1988 [3, 4]. It was primarily isolated from the pig brain, and thus was called brain natriuretic peptide. However, it was soon found that BNP is synthesized in the ventricular myocytes. In humans, this peptide is made up of 32 amino acids. In 1990, C-type natriuretic peptide was isolated from the pig brain. It is produced mainly in the central nervous system and vessels [5, 6]. In humans, the CNP chain consists of 22 amino acids [7]. D-type natriuretic peptide was isolated from the venom of the green mamba. Structurally, it is similar to ANP, BNP and CNP [8, 9]. In humans, DNP is present in the atrial cells and the plasma [10]. Urodilatin is also included in the family of natriuretic peptides. It is a 32-amino acid paracrine hormone that was isolated from human urine in 1988. Its structure is nearly identical to that of ANP; the difference is the 4 additional amino acids in the N-terminal fragment, urodilatin. This is not surprising, because ANP and urodilatin are formed as the results of cleavage of the same peptide: proANP (1-126). Urodilatin is produced by the renal tubule cells and acts exclusively in the kidneys. Some authors consider it to be a renal form of ANP. A peptide with the function of constricting the blood vessels was first discovered by Hickey et al. [11]. A few years later, the sequence of this peptide was determined [12]. Called endothelin (ET), it appeared to be identical in humans, dogs, rats and pigs. The activities of natriuretic peptides and endothelins are relatively strictly associated with each other. ANP and BNP are peptides that inhibit endothelin-1 production. On the other hand, ET-1 stimulates natriuretic peptide synthesis [13]. This specific self-control is found in many diseases of the circulatory system. In pathological conditions, the predominance of one of these systems in patients can be identified, and sometimes counteracted effectively, after the determination of the plasma concentrations of the defined natriuretic peptides and endothelins. NATRIURETIC PEPTIDES All natriuretic peptides are synthesized from polypeptide precursors. ANP, BNP and CNP have very similar structures. Each of them has a ring consisting of 17 amino acids, of which 11 are identical [14]. Urodilatin and ANP have an identical ring (Fig. 1). CELLULAR & MOLECULAR BIOLOGY LETTERS 157 Fig. 1. PDB model of an antrial natriuretic peptide var 1 (DOI 10.2210/pdb1anp/pdb), and a sequence homology of a loop structure of three main natriuretic peptides with the precursor, peptide, Urodilatin. Sequence similarity is indicated by dashed lines, and identical sequences of a loop are in black. Atrial natriuretic peptide is first synthesized in the atrial cells. A low concentration of ANP was also found in the ventricular cells and kidneys. However, compared to the myocardium, the ANP concentration in the kidney is negligible. ANP is synthesized in the form of a biologically inactive propeptide, proANP, which consists of 126 amino acids. This peptide undergoes cleavage by endoprotease (membrane serine protease) in the endoplasmic reticulum, into the biologically active C-terminal fragment, proANP (99-126) (also called alpha- ANP) (1-98). Alpha ANP is rapidly eliminated from the plasma; its half-life is 3-4 minutes. The Nt-pro-ANP half-life is significantly longer (60-120 min). Brain natriuretic peptide is mainly synthesized in the ventricular cells. BNP derives from the prepro-BNP precursor consisting of 134 amino acids. After cleavage, prepro-BNP splits into a 108-amino acid pro-BNP (1-108) and a 26-amino acid signal peptide (109-134). In turn, pro-BNP splits into the biologically active 32-amino acid C-terminal fragment, BNP (77-108), and the inactive 76-amino acid N-terminal fragment, Nt-proBNP (1-76) [15-19]. BNP has a half-life of about 20 minutes. The half-life of Nt-pro-BNP is significantly longer (60-120 min). C-type natriuretic factor is found in the central nervous system, the endothelial cells and in low concentrations in the blood plasma. It plays the role of the 158 Vol. 13. No. 2. 2008 CELL. MOL. BIOL. LETT. paracrine hormone. CNP is produced from the precursor pro-CNP as the result of cleavage by endoprotease. The atrial and ventricular cells are potent stimuli of ANP and BNP release. Both ANP and BNP are stored in granules and secreted via regulatory pathways from the atria. They are also secreted via the constitutive pathway from the ventricles. ANP is immediately released from atrial cell granules, which, coupled with its very short half-life, results in dynamic changes in its concentration in the blood. The secretion of BNP is mainly from the left ventricular cardiomyocytes, is controlled at the transcription level, and requires longer-lasting stimuli. An increased BNP concentration in the blood remains for a significantly longer time than an increased ANP concentration. Tachycardia is a factor that intensifies natriuretic peptide synthesis. Glycocorticosteroids, thyroid hormones, endothelin-1 and angiotensin II also increase this synthesis. Endothelin-1 and angiotensin II intensify the synthesis independently of their haemodynamic activity. CNP secretion is regulated by growth factors and cytokines, mainly by TNF-α, interleukin-1, basic fibroblast growth factor, and transforming growth factor β. Increased CNP secretion is observed as the result of tissue damage or hypoxia. Natriuretic peptides are ligands for three types of natriuretic receptors: type-A, type-B and type-C. These receptors are localized on the target cell surfaces. Type-A and type-B receptors have two extracellular domains binding the ligand, and two intracellular domains containing guanyl cyclase and kinase, which condition the formation of cGMP (cyclic guanosine monophosphate). Type-A and type-B receptors are responsible for the majority of the known biological activities of natriuretic peptides [20, 21]. Type-C receptors clear the natriuretic peptide from the circulation (clearance receptors). ANP and BNP mainly bind with type-A receptors, and CNP with type-B receptors [22]. ANP has the highest affinity to type-A receptors. It also shows a high affinity to type-C receptors. Natriuretic peptides are cleared from the circulation with the help of a clearance receptor (type-C receptor), and thanks to endopeptidases present on the surfaces of the epithelial cells, smooth muscles, myocytes, renal epithelium and fibroblasts. ANP and BNP are secreted from cardiac myocytes in response to atrial or ventricular wall stretch. The activity of ANP and BNP is similar. They increase
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