Pulmonary hypertension (PH) is a complex multifactorial disease with a multitude of presentations, associated diagnoses, and underlying causes. The WHO has classified PH into 5 clinical groups, and as a testament to the complexity of the disease these classifications are frequently modified, most recently in 2013. As a neonatologist, I am very interested in the complications of preterm birth and the most common complication is bronchopulmonary dysplasia (BPD), which is a chronic lung disease that affects these former preterm infants well into adulthood. The WHO classification system puts BPD-associated PH in group 3 or PH associated with respiratory disease. The pathogenesis of PH can involve many different cellular mechanisms, but most forms of PH, including BPD-associated PH, involve converging biochemical pathways. The pathway that I have become interested in due to its pivotal involvement in both vasoconstriction and vascular remodeling (the hallmarks of PH) is the L-arginine/NO pathway. L-arginine can be metabolized by nitric oxide synthase (NOS) to make the potent vasodilator NO, or by arginase, the first step in polyamine and proline synthesis, vital for the cellular proliferation that occurs during vascular remodeling. Asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, can be degraded by NG, NG-dimethylarginine dimethylaminohydrolase (DDAH), allowing for enhanced endogenous NO production in endothelial cells. Single nucleotide polymorphisms (SNPs) in the L-arginine/NO pathway have been associated with systemic hypertension and lung diseases, however their role in PH and specifically, BPD-associated PH, have not been studied. Our preliminary clinical data indicates, for the first time, that there are biomarkers involved in the L- arginine/NO pathway that may be differentially expressed in preterm infants that go on to develop BPD- associated PH compared to patients with BPD who do not develop PH. Indeed, we have 3 recent publications demonstrating differential expression; a SNP in the arginase 1 (ARG1) gene, plasma ADMA levels, and a SNP in the DDAH1 gene. Our goal is to take these novel, exciting, and important preliminary clinical findings and complete a series of studies in order to provide targeted research training, characterizing cellular mechanisms underlying the potential effects of ARG1 and DDAH1 in vitro, as well as identifying potential therapeutic strategies to either prevent or treat BPD-associated PH in an animal model of BPD-associated PH. We will achieve this goal through a structured training program that revolves around our translational research strategy which has 3 specific aims: 1) to test the hypothesis that inhibiting ARG1 function will increase NO production in pulmonary endothelial cells; 2) to test the hypothesis that inhibiting DDAH1 function will decrease NO production in pulmonary endothelial cells; 3) to test the hypothesis that a conditional mouse knock-out of ARG1 will attenuate PH, while a conditional mouse knock-out of DDAH1, will exacerbate PH, in a mouse model of BPD-associated PH. Our goal is to explore the potential for ARG1 and/or DDAH1 as innovative therapeutic targets for BPD-associated PH.

Public Health Relevance

Bronchopulmonary dysplasia (BPD)- associated pulmonary hypertension (PH) is a life- threatening neonatal disease characterized by progressive vascular endothelial dysfunction and smooth muscle cell proliferation. Currently, there are no available predictive biomarkers or curative therapies for BPD-associated PH. This proposal aims to discover the mechanism of potential biomarkers (arginase-1 and NG,NG-dimethylarginine dimethylaminohydrolase-1) in the L-arginine/nitric oxide pathway in order to precisely target treatment to improve the outcomes of this currently devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL129080-03
Application #
9538244
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Natarajan, Aruna R
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Trittmann, Jennifer K; Velten, Markus; Heyob, Kathryn M et al. (2018) Arginase and ?-smooth muscle actin induction after hyperoxic exposure in a mouse model of bronchopulmonary dysplasia. Clin Exp Pharmacol Physiol 45:556-562
Trittmann, J K; Bartenschlag, A; Zmuda, E J et al. (2018) Using clinical and genetic data to predict pulmonary hypertension in bronchopulmonary dysplasia. Acta Paediatr 107:2158-2164
Trittmann, Jennifer K; Gastier-Foster, Julie M; Zmuda, Erik J et al. (2016) A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia. Acta Paediatr 105:e170-5
Trittmann, Jennifer K; Jin, Yi; Chicoine, Louis G et al. (2016) An arginase-1 SNP that protects against the development of pulmonary hypertension in bronchopulmonary dysplasia enhances NO-mediated apoptosis in lymphocytes. Physiol Rep 4:
Nelin, Leif D; White, Hilary A; Jin, Yi et al. (2016) The Src family tyrosine kinases src and yes have differential effects on inflammation-induced apoptosis in human pulmonary microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 310:L880-8
Trittmann, Jennifer K; Peterson, Eric; Rogers, Lynette K et al. (2015) Plasma asymmetric dimethylarginine levels are increased in neonates with bronchopulmonary dysplasia-associated pulmonary hypertension. J Pediatr 166:230-3
Trittmann, J K; Nelin, L D; Zmuda, E J et al. (2014) Arginase I gene single-nucleotide polymorphism is associated with decreased risk of pulmonary hypertension in bronchopulmonary dysplasia. Acta Paediatr 103:e439-43
Trittmann, J K; Nelin, L D; Klebanoff, M A (2013) Bronchopulmonary dysplasia and neurodevelopmental outcome in extremely preterm neonates. Eur J Pediatr 172:1173-80