Heart failure is a leading cause of morbidity and mortality in the United States. Despite a number of important therapeutic advances for the treatment of symptomatic heart failure, the prevalence, mortality, and cost associated with heart failure continue to grow in the United States and other developed countries. Moreover, in utero and neonatal heart failure has been understudied despite a move towards fetal cardiac intervention, as mortality is higher and myocardial damage more serious in unoperated children or those undergoing delayed surgery. We uncovered a unique role for Pax3 transcription factor in specifying neural crest-derived sympathetic nervous system and maintaining catecholamine levels, such that when reduced, it results in 100% in utero lethality and diminished cardiac function. Preliminary data revealed that both adrenaline and tyrosine hydroxylase (primary enzyme involved in catecholamine synthesis) levels are suppressed in Pax3 nulls, as well as pERK and cAMP levels. Significantly, both isoproterenol (a synthetic catecholamine) and forskolin (increases intracellular cAMP) supplementation upregulate pERK and cAMP levels and prevent in utero lethality. Similarly, 60% oxygen hyperoxia exposure in utero also prevents in utero lethality. Furthermore, the physiological hyperoxia prevention of in utero lethality also upregulates pERK, suppresses elevated p38 and abolishes ectopic iNOS expression in rescued mutant hearts. This proposal is designed to apply this knowledge to a further understanding of the downstream effect of cardiac neural crest deficiency on in utero cardiac output via regulating catecholamine levels and affecting G-protein coupled receptor signaling. We hypothesize that neural crest-dependent signaling pathways are required for in utero survival and preservation of embryonic cardiac output, and that loss of Pax3-specification of neural crest results in poor contractility/heart failure and is an indirect result of the hypoxic environment and diminished cAMP levels. The ready availability of a genetically defined mouse mutant that can be rescued to term via oxygen supplementation, affords us a unique opportunity to understand neural crest-dependent effects upon in utero survival, cardiac contractility and embryo development;as well as determine some of the key heart failure signaling pathways involved. Thus, determining whether maternal oxygen and/or catecholamine supplementation are useful therapies to prevent congenital heart failure is the overall goal of these studies.

Public Health Relevance

Heart failure frequently complicates congenital heart disease in children and our proposal will focus on developing novel avenues to advance therapeutic strategies for pharmacological treatment of heart failure in utero. Specifically, we have found that Pax3 knockout mouse lethality (exhibiting structural conotruncal and interventricular septal defects as well as severe bradycardia) can be rescued by pharmacological administration of the adrenergic agonist isoproterenol (synthetic catecholamine), forskolin (increases intracellular cAMP levels), as well as physiologically via 60% hyperoxia treatment. As each of these treatments result in restoration of normal levels of Erk1/2 phosphorylation, our goal is to identif the mouse embryo cell types and Erk1/2 signaling pathways that respond to these pharmacological and physiological treatments, in order to uncover the underlying mechanisms affecting in utero cardiovascular function and their requirement for survival prior to birth.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL060714-14A1
Application #
8758931
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
1998-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
14
Fiscal Year
2014
Total Cost
$390,000
Indirect Cost
$140,000
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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