Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, affecting approximately one-third of extremely low birthweight infants[1, 2]. Pulmonary hypertension (PH), right ventricle hypertrophy (RVH) and RV failure further complicate the disease in 25-45% of infants with moderate to severe BPD, increasing morbidity and mortality[3-5]. Little is known about how to best treat BPD-associated PH, and current treatments are minimally effective. Mortality for infants with BPD-associated PH is reported to be as high as 50% by 2 years old, and these infants have a 4.6-fold risk of death compared to matched patients with BPD and no PH[3, 6]. The presence of RVH and RV failure negatively influences patient outcomes. There is a gap in knowledge of the molecular mechanisms and pathophysiology leading to the development of BPD-associated PH and its ultimate impact on the RV. The nitric oxide-cyclic-guanosine monophosphate (NO-cGMP) signaling pathway is important in the regulation of smooth muscle tone, and the presence of reactive oxygen species (ROS) can alter this pathway leading to vasoconstriction and abnormal lung and pulmonary vascular development[7-9]. Vasoconstriction and vascular remodeling lead to an increase in pulmonary vascular resistance (PVR), thus increasing afterload and strain on the RV. However, virtually nothing is known about cGMP signaling in the neonatal RV and any direct impact it may have on RVH and RV failure in BPD-associated PH. In the heart, cGMP and cyclic adenosine monophosphates (cAMP) are known to be important intracellular second messenger molecules involved in the regulation of cardiovascular homeostasis. Their roles are multi-faceted, and they achieve different effects by compartmentalization within the cardiomyocyte [11-13]. cGMP negatively modulates contractility and accelerates relaxation of cardiomyocytes, affecting lusitropy and inotropy. Phosphodiesterases (PDE) are a large group of enzymes that are important downstream targets for cyclic nucleotide signaling. In the cardiomyocytes, PDE1, PDE2, PDE3 and PDE5 are known to regulate cAMP and cGMP hydrolysis. PDE5 is a cGMP-specific PDE and is upregulated in adult mouse models of RV and LV failure[15, 16]. PDE5 inhibitors increase RV inotropy in animal models of heart failure and in human clinical data . We have previously demonstrated that hyperoxia and increased ROS alter key members of the cGMP pathway such as PDE5 in pulmonary artery smooth muscle cells[17, 18], and others have demonstrated that ROS alter cardiac fibroblast proliferation and contractile dysfunction. Thus, our hypothesis is that hyperoxia exposure increases ROS, which in turn disrupts the cGMP signaling pathway in neonatal cardiomyocytes leading to upregulation of cardiac PDE5, RVH and RV dysfunction.
|Effective start/end date||7/1/14 → 6/30/15|
- American Academy of Pediatrics (MKPRA2014)
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