Heart failure (HF) is a leading cause of death globally, affecting almost 6 million people in the United States alone. Up to 50% of these patients will die within five years of diagnosis, making elucidation of the mechanistic underpinnings imperative so they can be evaluated for therapeutic potential. Evidence from our lab has shown that phosphodiesterases (PDEs) that degrade cyclic guanosine monophosphate (cGMP) have great utility as druggable targets in heart failure. These PDEs ultimately block protein kinase G (PKG) signaling, a known cardioprotective pathway; hence blockade of PDE activity results in cardioprotection. Several cGMP-specific PDEs are present in the heart, namely the nitric oxide-linked PDE5a and the natriuretic peptide-linked PDE9a. These PDEs are compartmentalized to specific regions of the cell, although little is known about this compartmentation for PDE5, and nothing is known for PDE9. Part of this proposal aims to study this compartmentation using novel molecular tools such as compartment-targeted PKG inhibitors and tagged PDEs that can be used to determine subcellular localization and compartment-specific proteomes. Knowing the specifics of the PDE5 and PDE9 compartments may clarify how these PDEs can be manipulated for therapeutics. Previous in vivo studies have demonstrated that inhibition of PDE5 has great therapeutic utility in male animal HF models, but has fallen short in female mice lacking estrogen (comparable to HF in postmenopausal women) and in human HF with preserved ejection fraction patients. These shortcomings are due to the regulation of nitric oxide by estrogen and the depression of nitric oxide levels in HF, respectively. Recently we revealed that inhibition or genetic deletion of PDE9a, the other cGMP-specific PDE in the heart, attenuates cardiac hypertrophy in male mice. The PDE9 pathway acts independently of the nitric oxide/PDE5 pathway, making it a promising drug target in situations where PDE5 inhibition is ineffective. We hypothesize that inhibition of PDE9 will result in improved cardiac function in rodent pressure-overload models independent of sex and sex hormone status. This hypothesis will be tested in a female pressure-overload HF model using C57Bl6 mice treated with PDE9 inhibitors and PDE9a knockout mice lacking estrogen.
Phosphodiesterases are known to be compartmentalized within the cell. In the heart, the cGMP- specific phosphodiesterases PDE5a and PDE9a have both been shown to play a role in cardiac disease through the signaling enzyme protein kinase G. However, compartment and signaling differences between these two PDE isoforms and how they can be leveraged for heart failure therapy are currently poorly understood.