Pulmonary Arterial Hypertension (PAH) is a devastating disease characterized by increased pulmonary artery pressures, pulmonary vascular resistance, vascular remodeling, and right ventricular (RV) failure. Right ventricular failure is the cause of mortality associated with PAH, and is associated with maladaptive RV remodeling and fibrosis. The cardiac fibroblasts (CF) play a key role in cardiac remodeling and fibrosis through proliferation and matrix generation. Our preliminary data suggests that non-neuronal acetylcholine (ACh) synthetic pathway and a7-nicotinic acetylcholine receptor (nAChR) pathway in the failing right ventricle is upregulated, interacts with pro-fibrotic angiotensin II signaling, and thus may be an important mechanism and a novel target to inhibit ventricular fibrosis and dysfunction. However, the role of nAChRs in CF and in myocardial fibrosis associated with PH remains unknown. We hypothesize that activation of a non-neuronal nAChR pathway in the CF in PAH causes RV fibrosis and failure. If this is correct, chemical inhibition of nAChR should result in improvement of RV function in a preclinical model of PAH. In order to test this hypothesis we propose the following Specific Aims:
Specific Aim 1 : We will elucidate the role and underlying mechanism of Ach/nAChR in mediating CF proliferation and collagen synthesis. We will characterize the Ach/nAChR expression in preclinical model of severe PH and RV dysfunction/fibrosis and determine the signaling mechanism associated with increased CF proliferation and collagen synthesis in response to nAChR activation.
Specific Aim 2 : We will determine the role of nAChR in angiotensin II signaling resulting in CF proliferation and collagen synthesis and elucidate the mechanism(s) of interaction. We will use primary isolated cardiac fibroblasts in in vitro assays to elucidate the cooperative signaling mechanism between the nAChR and angiotensin type 1 receptor (AT1R).
Specific Aim 3 : We will determine the effect of inhibiting nAChR on RV fibrosis and function and exercise capacity in a preclinical model of PAH. The approach used in this aim is to treat animals with PH with nAChR and AT1R antagonists to evaluate the efficacy of nAChR antagonism on RV fibrosis and function. These studies will delineate a novel signaling pathways leading to the increased fibrosis observed in the RV in PAH and will provide data on the efficacy of nAChR antagonism on RV function in PAH. The results from these experiments will inform us in designing a pilot translational study evaluating the efficacy and safety of use of clinically available nAChR antagonists in patients with RV dysfunction in settings of PAH.

Public Health Relevance

Pulmonary arterial hypertension is devastating disease associated with poor outcomes. In patients with pulmonary arterial hypertension, poor right heart function is associated with increased mortality. Cardiac fibroblasts are cells that play a ke role in heart remodeling and fibrosis. Increased proliferation and extracellular matrix synthesis by cardiac fibroblasts in the right heart can cause right heart dysfunction and failure. However, no drugs are available that target the pathology in right heart. In this project, we investigate a novel mechanism that may underlie right heart fibrosis and dysfunction, and test a treatment strategy that can improve the heart function in setting of pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128661-03
Application #
9285830
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2015-09-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$332,422
Indirect Cost
$69,686
Name
Ocean State Research Institute, Inc.
Department
Type
Research Institutes
DUNS #
848476271
City
Providence
State
RI
Country
United States
Zip Code
02908
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