Pulmonary arterial hypertension (PAH) is a disease characterized by the progressive remodeling of the distal pulmonary arteries, resulting in the loss of vascular cross-sectional area and elevated pulmonary vascular resistance. Without intervention, PAH is usually progressive, leading to right heart failure and death. Pulmonary vascular remodeling includes the proliferation and migration of pulmonary artery smooth muscle cells, endothelial cells and fibroblasts. Several studies have shown that increasing intracellular cyclic adenosine monophosphate (cAMP) levels result in a reduction of vascular cells proliferation in vitro and in vivo, and it has recently been discovered that members of the ATP-binding cassette (ABC) transporters family can actively transport cAMP out of cells. Moreover, we recently reported secreted cardiomyocyte-cAMP into the extracellular space to be an important paracrine factor in the myocardium that also protects the heart from adrenergically induced hypertrophy and fibrosis. Extracellular cAMP is metabolized to adenosine, which activates its receptors that are expressed in several cells. Because adenosine is known to be a potent inhibitor of vascular remodeling (through its Gs protein-coupled receptors), we aim to study the presence of the extracellular cAMP pathway in pulmonary vascular cells. Our goal is to attenuate pulmonary vascular remodeling by using the extracellular cAMP pathway as a therapeutic approach to reverse the pathological changes in PAH.
The specific aims of this proposal are: 1) to define the presence of the extracellular cAMP pathway in pulmonary artery cells, 2) to evaluate the effects of extracellular cAMP on vascular cells proliferation and migration, as well as determining its mechanism, 3) to assess the effects of endogenous secreted-cAMP in pulmonary vascular cells and 4) to investigate the impact of extracellular cAMP infusion in in vivo models of PAH. Defining the presence and the mechanisms of the extracellular cAMP pathway and its physiological consequences will be of great relevance in the analysis of the PAH disease. Targeting the extracellular cAMP pathway might be a useful strategy to prevent and treat pulmonary hypertension.

Public Health Relevance

Pulmonary hypertension (PH) is a life-threatening and often fatal disease, and novel therapeutic approaches directly targeting the vascular remodeling process are warranted. We recently reported the presence of an extracellular cyclic adenosine monophosphate (cAMP) pathway in the myocardium that protects the heart from cardiac remodeling. Defining the presence and mechanisms of the extracellular cAMP pathway, as well as its physiological consequences will be of great relevance in the analysis of PH; the significance of this proposal is driven by the potential impact of identifying a novel therapy to prevent PH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01HL135474-01A1
Application #
9375247
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2018-03-20
Project End
2023-02-28
Budget Start
2018-03-20
Budget End
2019-02-28
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029