Cyclic nucleotide signaling is key to fundamental physiologic responses, like the fight-or-flight response. Phosphodiesterase 1 (PDE1) hydrolyzes cyclic nucleotides cAMP and cGMP, and is a major regulator of cardiac contractility. The lack of specific inhibitor, however, hampered our understanding of its cardiovascular role, and especially in the context of cell contractility. The development of a highly-specific drug changed this.
Using this novel compound, we showed:
The improvement of vascular resistance and cardiac contractility in rabbit and dog, as well as in a pacing-induced heart failure model in the latter.
These effects were notably absent in mice, whose hearts express a different profile of PDE1 isoform expression compared to larger mammals, including humans.
Individual myocytes show improved contractility.
A unique profile of calcium handling alterations - increased sarcolemmal calcium channel activation that did not further change sarcoplasmic reticulum calcium handling or calcium sensitivity of myofilaments.
Our work spawned a clinical phase:
Completed in 2021, a Phase Ib/IIa trial in patients with heart failure showed that the compound improves vascular resistance and cardiac contractility.
Our research program investigates the cell signaling pathway that mediates PDE1 actions in the myocardium. Using animal models (mouse and guinea pig), primary and cultured heart cells, biochemical assays, and state-of-the-art Forster resonance energy transfer (FRET) imaging techniques, we are examining:
Upstream complexes that contribute to PDE1 localization
Downstream proteins that mediate PDE1 signaling
The compartmentalized nature of PDE1 signaling
What happens in the setting of heart disease?
Because PDE1 inhibitors are also under evaluation for cancer and neurodegenerative diseases, our mechanistic findings are also likely to advance the understanding and treatment of these diseases.