Emerging Roles of Natriuretic Peptides and their Receptors in Pathophysiology of Hypertension and Cardiovascular Regulation

Abstract

Thus far, three related natriuretic peptides (NPs) and three distinct receptors have been identified, which have advanced our knowledge towards understanding the control of high blood pressure, hypertension, and cardiovascular disorders to a great extent. Biochemical and molecular studies have been advanced to examine receptor function and signaling mechanisms and the role of second messenger cGMP in pathophysiology of hypertension, renal hemodynamics, and cardiovascular functions. The development of gene-knockout and gene-duplication mouse models along with transgenic mice have provided a framework for understanding the importance of the antagonistic actions of natriuretic peptides receptor in cardiovascular events at the molecular level. Now, NPs are considered as circulating markers of congestive heart failure, however, their therapeutic potential for the treatment of cardiovascular diseases such as hypertension, renal insufficiency, cardiac hypertrophy, congestive heart failure, and stroke has just begun to unfold. Indeed, the alternative avenues of investigations in this important are need to be undertaken, as we are at the initial stage of the molecular therapeutic and pharmacogenomic implications.

Keywords: Natriuretic peptides; cardiovascular events; gene-targeting; natriuretic peptide receptors.

Figure 1. Natriuretic peptide hormone family

Amino-acid sequence and comparison of human ANP, BNP, and CNP with conserved residues represented by red boxes. The lines between two cysteine residues in ANP, BNP, and CNP molecules indicate a 17-amino acid disulfide bridge, which is essential for the biological activity of these peptide hormones.

Figure 2. Diagramatic representation of ligand specificity, transmembrane topology and signaling system of natriuretic peptide receptor-A, -B, and -C (NPRA, NPRB, and NPRC), respectively

The arrows indicate the specificity of ligand to specific NPs receptor. The extracellular ligand binding domain (LBD), transmembrane region, and intracellular protein kinase-like homology domain (KHD) and guanylyl cyclase catalytic domain (GCD) of NPRA and NPRB are indicated. Similarly, ligand binding domain, transmembrane region, and short intracellular tail of NPRC are also indicated. Both NPRA and NPRB are shown to bind ATP in protein-KHD and to generate second messenger cGMP from GTP hydrolysis. An increased level of intracellular cGMP stimulates and activates three known cGMP effecter molecules namely; cGMP-dependent protein kinases (PKGs), cGMP-dependent phosphodiesterases (PDEs), and cGMP-gated or cyclic nucleotide gated-ion channels (CNGs). The activation of PKGs, PDEs, and/or CNGs elicits physiological responses including: vasodilation, sodium and water excertion, antiproliferation, and antihypertrophic effects. One or more specific physiological responses lead to renoprotection, cardioprotection and/or vasoprotection. ANP binding to NPRC has been suggested to increase inositoltrisphosphate (IP3) and to decrease cAMP levels in target tissues and cells.