The goal of this proposal is to develop a thorough understanding of the regulation of the two subtypes of
phosphodiesterase 3 (PDE3) in cell culture and murine models of pulmonary hypertension (PH). The long-term
objectives are to delineate the function and mechanistic pathways regulated by each of the PDE3 subtypes,
PDE3A and PDE3B that are implicated in PH pathobiology for the development of potential therapeutic targets.
PH is a life-threatening disease characterized by vascular remodeling, smooth muscle cell (SMC) proliferation,
and endothelial cell dysfunction that results in decreased luminal diameter, increased pulmonary vascular
resistance, increased right ventricular pressures, progressive right heart failure and premature death. PDE3
hydrolyzes cAMP and cGMP, which are critical second messengers that regulate signal transduction pathways
resulting in vasodilation. PDE3A and PDE3B have differential expression and function; therefore, we postulate
they have distinctive roles and mechanistic actions in the pulmonary vasculature. PDE3A is implicated to be
the important isoform in VSMC proliferation, while PDE3B plays an important role in energy metabolism. Thus,
we hypothesize that it is through these discrete pathways that alterations in PDE3 play a role in PH. Persistent
pulmonary hypertension of the newborn (PPHN) is a disease in which failure of the normal circulatory transition
at birth results in high pulmonary vascular resistance, low pulmonary blood flow and abnormal gas exchange.
Inhaled nitric oxide (iNO) is the only FDA-approved pharmacologic pulmonary vasodilator to treat patients with
PPHN. However, ~50% of infants with PPHN have a suboptimal response to iNO. The mechanisms for poor
iNO response in these patients have yet to be elucidated. In vitro and in vivo studies demonstrate that
exposure of iNO to the vasculature promotes PDE3 expression and/or activity suggesting the possibility that
PDE3 activity may be the reason for the poor response. Therefore, in this proposal, we aim to define the role of
each PDE3 subtype in murine models of PH utilizing PDE3A knockout and PDE3B knockout mice, as well as
interrogate the interactions between two critical pathways involved in the pathobiology of PH: the NO-cGMP
and cAMP-PDE3 pathways – both upon which primary therapeutic modalities for PH are based. Finally, we
propose to perform a prospective, observational cohort study to evaluate whether any clinical, biochemical
and/or genetic biomarkers can predict which patients with PPHN will be nonresponsive to iNO therapy.
Identifying and understanding the factors associated with a poor response to iNO therapy in these patients
could lead to improved and personalized clinical decision-making that results in better patient outcomes, the
identification of potential novel targets for therapy, and lower healthcare costs. Through this proposal, we will
ultimately gain a better understanding of the underlying pathophysiology of PH that will allow us to design
rational therapy plans to treat the disease.