Gene wiki reviewAtrial natriuretic peptide in cardiovascular biology and disease (NPPA)
Introduction
Maintaining salt-water balance is of fundamental importance for all animals. The discovery of the natriuretic activity in rat atrial extracts by de Bold et al. established a previously suspected cardiac endocrine function in regulating body fluid homeostasis (de Bold et al., 1981). The responsible molecule later was found to be atrial natriuretic factor (ANF), also called atrial natriuretic peptide (ANP) (de Bold, 1985). Under high blood volume and pressure, heart muscle cells release ANP into the circulation. In the kidney, ANP enhances salt and water excretion. In the blood vessel, ANP promotes vasodilation. As such, ANP acts as a cardiac hormone to regulate blood volume and pressure. Defects in the ANP pathway are now known to contribute to major diseases such as hypertension, cardiac hypertrophy and heart failure (HF). More recently, ANP and related peptides have been implicated in lipid metabolism and metabolic disease. In this review, we discuss the role of ANP in cardiovascular biology and disease.
Section snippets
The NPPA gene
In mammals, the natriuretic peptide family has three members: ANP, brain or B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) (Potter et al., 2006, Wu et al., 2009). These peptides are encoded by three separate genes evolved from an ancestral natriuretic peptide gene in primitive vertebrates (Inoue et al., 2003, Takei et al., 2006). The human NPPA gene, encoding the ANP precursor, is on the short arm of chromosome 1 (1p36.21). The gene consists of 3 exons and spans more
ANP biosynthesis and processing
ANP is synthesized as a precursor, i.e. prepro-ANP, a polypeptide of 151 amino acids (Fig. 1). In the endoplasmic reticulum, signal peptidase removes the 25-amino-acid signal peptide, which may be further processed by signal peptide peptidase and released from the cell. Small fragments derived from the ANP signal peptide have been detected in human plasma (Pemberton et al., 2012). After the removal of the signal peptide, the 126-amino-acid pro-ANP is stored in the granules in cardiomyocytes.
Biological functions of ANP
The primary function of ANP is to promote natriuresis and diuresis in the kidney and to relax vascular smooth muscles, thereby regulating blood volume and pressure. This function is mediated by the natriuretic peptide receptor A (NPR-A), also called guanylyl cyclase A, a transmembrane receptor containing an intracellular guanylyl cyclase domain (Koller and Goeddel, 1992, Potter et al., 2006). Upon ANP binding, the receptor is activated, promoting cyclic guanosine monophosphate (cGMP)
NPPA variants in cardiovascular disease
NPPA variants are associated with plasma ANP concentrations, blood pressure levels and cardiovascular diseases (Lynch et al., 2009, Rubattu et al., 2014b). One of the variants, g.–664C>G, is in the 5′ promoter region (Fig. 2). In a European population, the G allele was associated with low plasma ANP levels and high risks of hypertension and cardiac hypertrophy (Rubattu et al., 2006, Rubattu et al., 2007). A similar finding was reported in a Japanese population (Kato et al., 2000).
The variant
ANP as a biomarker
The NPPA gene is up-regulated under physiological and pathological conditions. Mechanical stretch of the atrial wall is one of the most potent stimuli for ANP expression and release (Edwards et al., 1988). The signaling molecules in this process include integrins, p38 MAPK and focal adhesion kinase (Kerkela et al., 2011, Peng et al., 2008). To date, many growth factors and vasoactive molecules have been reported to enhance ANP expression and secretion (Ogawa and de Bold, 2014, Potter et al.,
ANP as a therapeutic agent
Given its unique pleiotropic functions in promoting natriuresis, diuresis and vasodilation and inhibiting aldosterone and renin secretion, ANP represents a promising drug candidate for cardiovascular disease such as HF. In fact, a recombinant form of human ANP, carperitide, has been approved in Japan to treat HF patients (Mitaka et al., 2011, Saito, 2010). The peptide also showed therapeutic benefits in patients with myocardial infarction and kidney disease (Kasama et al., 2007, Kitakaze et
Conclusions
Since the discovery of ANP in the 1980s, we have gained considerable insights into the gene expression, biosynthesis, post-translational processing and biological function of this peptide hormone. In addition to its role in promoting natriuresis, diuresis and vasodilation, ANP also regulates cardiac function, vascular remodeling and energy metabolism. These functions are of significant importance in maintaining cardiovascular and metabolic homeostasis. To date, common NPPA variants have been
Acknowledgments
This review and the corresponding Gene Wiki article are written as part of the Cardiac Gene Wiki Review series—a series resulting from a collaboration between the journal GENE, the Gene Wiki Initiative, and the BD2K initiative. The Cardiac Gene Wiki Initiative is supported by National Institutes of Health (GM089820 and GM114833). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. The authors would like to thank Nancy Fiordalisi for critical reading of this
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