Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity

Abstract

Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.

Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure

“…BAY 60-7550 was unable to augment the positive inotropic and chronotropic actions of ISO in this setting, establishing that metabolism of the pool of cAMP that regulates contractility and rate in sham or failing hearts is not a key role for PDE2; this dovetails well with a lack of effect of BAY 60-7550 on HR in vivo ( SI Appendix , Table S4 ). These data clearly demonstrate that the favorable effects of BAY 60-7550 are not underpinned by an acute action on cardiac contractility but, instead, are exerted via a more extensive, chronic influence on heart morphology [and potentially additional mechanisms, including autonomic regulation ( 55 , 56 )].…”

Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

“…Whilst there are always difficulties translating pre-clinical observations into patients, the insights offered from the studies of PDE2 also afford the potential of stratifying treatment and targeting PDE2 selectively, depending on the nature of pathology. For example, given the positive pharmacodynamic profile of PDE2i during pressure overload, as well as the recent observations that blocking PDE2 activity specifically within cardiac sympathetic neurons may be advantageous during sympathetic hyperactivity [101,102], inhibiting PDE2 may be effective in the context of HF and HT. Alternatively, enhancing PDE2 activity could perhaps help the failing heart post-MI.…”

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

“…Within the cardiovascular system, PDE2 is predominantly expressed in endothelial cells and in cardiac fibroblasts but is modestly expressed in cardiomyocytes under physiological conditions [ 133 , 143 , 144 ]. Prominent PDE2 expression is notable in various neuronal cell types within the central nervous system and thereby PDE2 activity in sympathetic neurons also modulates the cardiac function [ 145 , 146 , 147 , 148 ]. Furthermore, PDE2 activity was also demonstrated in circulating immune cells, e.g., monocytes, macrophages and lymphocytes [ 149 , 150 , 151 , 152 ].…”

“…PDE2 activity was also reported to be increased in stellate ganglion derived from patients with a sympathetic overdrive and ventricular arrhythmias. This also implicates that selective targeting of neuronal PDE2 may offer a novel potential therapeutic strategy in sympathetic hyperactivity disease settings [ 147 ].…”