The Endocrine Function of the Heart: Physiology and Involvements of Natriuretic Peptides and Cyclic Nucleotide Phosphodiesterases in Heart Failure

Figure 1. Interactions between natriuretic peptides and cyclic nucleotide pathways. By stimulating the NPR-A receptor, the natriuretic peptides ANP and BNP increase cGMP formation from guanosine triphosphate (GTP). This increase in cGMP, in addition to cGMP-protein kinase activation (PKG), might also activate PDE2 (which hydrolyses both cAMP and cGMP), inhibits PDE3 (which hydrolyses mainly cAMP, but also cGMP with a higher affinity), whereas it increases the activity cyclic nucleotide gated channels (CNGC). Below, receptor regulation modulating intracellular cyclic nucleotide levels and cyclic nucleotide phosphodiesterases (PDEs) very quickly hydrolyze cAMP and/or cGMP, controlling therefore the protein-kinase dependent phosphorylations (PKA and PKG), as well as CNGC in normal and physio-pathologic conditions. Reciprocally, PDE activity might be regulated by phosphorylation and by gene expression. In some physiopathologies, some PDE subtypes might be specifically altered, notably in cardiovascular diseases, opening new therapeutic approaches (see Section 2.4. and Reference [12]). 5′ AMP, 5′ adenosine monophosphate; cAMP, adenosine 3′,5′-cyclic monophosphate; ANP, atrial natriuretic…

Figure 2. The main physiological effects of cardiac natriuretic peptides (NPs) and mechanisms reducing their activities. ANP, atrial natriuretic peptide; AVP, arginine vasopressin; BNP, brain natriuretic peptide; cGMP, guanosine 3′,5′-cyclic monophosphate; NaCl, sodium chloride; NEP, neutral endopeptidase; NPR-A, natriuretic peptide receptor of type A; NPR-C, natriuretic peptide receptor of type C; PKG-I/II, protein kinase G of types I/II; mPTP, mitochondrial permeability transition pore; SNS, sympathetic autonomous nervous system.

Figure 3. Cyclic nucleotide phosphodiesterases family implications and therapeutic targets in cardiovascular diseases. Cardiovascular diseases alter specific PDE(s) either by increasing or decreasing PDE activity in a compartmentalized manner in conjunction with receptor responses. Not only might the cGMP pathway be impacted by natriuretic peptides, but also the cAMP pathway. Since PDE2 and PDE3, which are oppositely modulated by cGMP level, are both present in cardiomyocytes, dependently of their relative activities, they might also participate in the regulation of cardiac cGMP (see Figure 2). In that way, the alterations in natriuretic peptides might impact not only cGMP signaling, but also cAMP signaling. Thus, by overcoming specific characterized PDE alterations, it should be possible to restore a physiologic status by conceiving new PDE modulators, notably PDE inhibitors (PDEi). 5′ AMP, 5′ adenosine monophosphate; cAMP, adenosine 3′,5′-cyclic monophosphate; ANP, atrial natriuretic peptide; ATP, adenosine triphosphate; BNP, brain natriuretic peptide; 5′ GMP, 5′ guanosine monophosphate; cGMP, guanosine 3′,5′-cyclic monophosphate; GTP, guanosine triphosphate; PDE, cyclic nucleotide…