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.

Public Health Relevance

Pulmonary hypertension is a life-threatening disease characterized by thickening and changes in the blood vessel wall resulting in high blood pressure in the lungs that can lead to an increase in pressures on the right side of the heart, progressive right heart failure, and premature death. With no cure for pulmonary hypertension, this proposal addresses the underlying causes of the blood vessel wall changes seen in this disease in order to find new options for the prevention and treatment of pulmonary hypertension. In addition, an observational study will be performed to determine whether any clinical factors or biomarkers can predict response to therapy in these patients that can ultimately 1) guide clinical decision-making that can lead to better patient outcomes, 2) identify potential novel targets for therapy, and 3) decrease healthcare costs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Natarajan, Aruna R
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Nationwide Children's Hospital
United States
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