Understanding the complex inner workings of the heart is a crucial step towards developing effective treatments for cardiovascular disease. One important aspect is the way in which cells communicate with each other through the signalling molecule cAMP. This molecule is known to operate through compartmentalisation into tiny regions, or nanodomains, each with its own specific role in cell function. Each of these nanodomains is regulated by one, or a combination of, specific cAMP-hydrolysing enzymes called phosphodiesterases, which controls its function.
Research has linked disruption of these nanodomains to heart disease, demonstrating it is vitally important that cAMP functions correctly at the subcellular level. However, this research has largely focused on a small number of predictable subcellular locations, leaving much of the system unexplored. The detailed inner workings of the cAMP nanodomain organisation have therefore remained elusive.
A new Zaccolo group study has used an unbiased approach to uncover previously unseen cAMP nanodomains in cardiac myocytes. The team has conducted an integrated phospho-interactomics analysis of specific phosphodiesterase isoforms to unveil several novel cAMP nanodomains. One of these newly identified nanodomains is located within the nucleus and regulates cardiac myocyte hypertrophy, a process involved in the cardiac remodelling associated with heart failure. Researchers found that a specific type of phosphodiesterase called PDE3A2 is responsible for regulating this nanodomain through PKA-dependent regulation of HDAC1 activity. By inhibiting PDE3A2, researchers were able to trigger hypertrophy in both rodent and human heart cells.
PDE3 inhibitors are used in the clinic to treat heart failure, as the resulting increase in cAMP enhances the strength of contraction and the ejection fraction, helping the failing heart to pump sufficient blood to the peripheral tissues. However, despite the short-term beneficial effect, these drugs are well-known to be associated, via undefined mechanisms, with increased mortality in the long term, limiting their indication to cases of refractory, decompensated heart failure. Lead researcher Professor Manuela Zaccolo said: “Our finding that inhibition of nuclear PDE3A2 promotes cardiac remodelling provides a novel insight into the detrimental long-term effects associated with the administration of PDE3 inhibitors.
“Overall, our study contributes to a deeper understanding of the role of cAMP signalling in cardiac myocyte physiology and pathophysiology. The identification of the nuclear cAMP nanodomain regulated by PDE3A2 has implications for the treatment of heart failure and other cardiac diseases. Defective cAMP signalling through the beta-adrenergic system is a key determinant of exercise intolerance and reduced quality of life in cardiac patients. Our discovery sheds new light on the complex workings of cAMP signalling in the heart and provides a roadmap for developing targeted therapies to treat heart disease with subcellular precision. By extending this approach to other phosphodiesterases, it will be possible to unveil the full landscape of cAMP nanodomains present in the cardiac myocyte. This map will provide an invaluable framework for the development of targeted therapeutics that can modulate cAMP levels only in those nanodomains that are associated with beneficial effects leaving unperturbed those domains that are linked with negative side effects.”
The full paper “Integrated proteomics unveils nuclear PDE3A2 as a regulator of cardiac myocyte hypertrophy” is available to read in Circulation Research.
The paper is joint first authored by Dr Gunasekaran Subramaniam, Dr Katharina Schleicher, and Dr Duangnapa Kovanich.