Natriuretic peptides in cardiovascular diseases: current use and perspectives

Abstract

The natriuretic peptides (NPs) family, including atrial, B-type, and C-type NPs, is a group of hormones possessing relevant haemodynamic and anti-remodelling actions in the cardiovascular (CV) system. Due to their diuretic, natriuretic, vasorelaxant, anti-proliferative, and anti-hypertrophic effects, they are involved in the pathogenic mechanisms leading to major CV diseases, such as heart failure (HF), coronary artery disease, hypertension and left ventricular hypertrophy, and cerebrovascular accidents. Blood levels of NPs have established predictive value in the diagnosis of HF, as well as for its prognostic stratification. In addition, they provide useful clinical information in hypertension and in both stable and unstable coronary artery disease. Structural abnormalities of atrial natriuretic peptide gene (NPPA), as well as genetically induced changes in circulating levels of NPs, have a pathogenic causal link with CV diseases and represent emerging markers of CV risk. Novel NP-based therapeutic strategies are currently under advanced clinical development, as they are expected to contribute to the future management of hypertension and HF. The present review provides a current appraisal of NPs' clinical implications and a critical perspective of the potential therapeutic impact of pharmacological manipulation of this class of CV hormones.

Keywords: ARNi; Cardiovascular diseases; Genetics; NEP inhibitors; Natriuretic peptides; Natriuretic peptides analogues.

Figure 1

Schematic representation of natriuretic peptides structure, cleavage processing, and degradation. ProANP1-126 and signal peptide, cleaved to NT-proANP1-98 and the active hormone ANP1-28. Recognition of the mid-regional portion (amino acids 53–90, pink colour) within NT-proANP allows measurement of MR-proANP; ProBNP1-108 and signal peptide, cleaved to NT-proBNP1-76 and the active hormone BNP1-32; ProCNP1-103 and signal peptide, cleaved to NT-proCNP1-80(50) and the active hormones CNP1-53 and CNP1-22. Red and purple arrows indicate processing sites by furin and corin. Blue and green arrows indicate NPs degrading enzymes: neutral endopeptidase (NEP), dipeptydil peptidase IV (DPPIV), and insulin degrading enzyme (IDE).

Figure 2

Natriuretic peptides produced by cardiomyocytes (CM) upon haemodynamic and neuroendocrine regulation act on target cells through specific receptors, soluble guanylyl cyclase (sGC), type A and B (GC-A and GC-B). The type of biological effect mediated by each receptor through the cGMP pathway, involving protein kinase G (PKG) and phosphodiesterase (PDE), is described. C-type natriuretic peptide produced by endothelial cells (EC) acts through GC-B and also through natriuretic peptide receptor (NPR-C), a non-GC receptor able to inhibit adenylate cyclase (AC) and to reduce cAMP levels. The biological effects of NPR-C within the cardiovascular system are shown. NPR-C plays also a fundamental role in NPs clearance.

Figure 3

Both renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS) blockade represent established therapeutic tools for controlling cardiovascular function and structure, and they both lead to improved outcome of heart failure (HF), hypertension (HT), and coronary artery disease (CAD). The pharmacological modulation of NPs family represents an emerging target to combat CVDs and their outcomes. It is expected to integrate the effects obtained by both RAAS and SNS blockade and to contribute to optimize control of CVDs and of their outcomes (dashed line). CO, cardiac output; SVR, systemic vascular resistance; BP, blood pressure.