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.

• Authors: Kun Liu, Dan Li, Guoliang Hao, David McCaffary, Oliver Neely, Lavinia Woodward, Demetris Ioannides, Chieh-Ju Lu, Marcella Brescia, Manuela Zaccolo, Harikrishna Tandri, Olujimi A Ajijola, Jeffrey L Ardell, Kalyanam Shivkumar, David J Paterson
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 9 (05 03 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 29720569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Natriuretic Peptide, Brain
• Cyclic Nucleotide Phosphodiesterases, Type 2
• Cyclic GMP
• Calcium
• Norepinephrine

Topics

• Adult
• Aged
• Animals
• Arrhythmias, Cardiac (enzymology, physiopathology)
• Autonomic Nervous System Diseases (metabolism, physiopathology)
• Calcium (metabolism)
• Case-Control Studies
• Cyclic GMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (antagonists & inhibitors, genetics, metabolism)
• Electromagnetic Fields
• Female
• Heart (physiopathology)
• Humans
• Male
• Middle Aged
• Natriuretic Peptide, Brain (pharmacology)
• Neurons (enzymology, metabolism)
• Norepinephrine (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Stellate Ganglion (enzymology, pathology)
• Synaptic Transmission
• Ventricular Function
• Young Adult