Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. PAH arises from different etiologies that share common pathophysiological features including remodeling of the pulmonary vessel wall, vasoconstriction, and thrombosis 1. This application focuses on the mechanism by which carbon monoxide (CO) exerts its therapeutic actions in a murine model of experimental pulmonary hypertension. Recent data reveals that CO is a critical effector molecule in ameliorating the progression and/or hastening the regression of vascular pathology in experimental pulmonary hypertension. Preliminary studies demonstrate linkage between the anti-proliferative actions of CO and its ability to prevent growth factor-induced downregulation of cav-1, a putative tumor suppressor gene. In addition cav-1 is an important regulator of endothelial nitric oxide synthase (eNOS) and is required for agonist and shear stress-stimulated NO production from eNOS. In the context of PAH, recent studies reveal downregulation of cav-1 and decreased eNOS activity in pulmonary hypertension. A central hypothesis provides focus to the proposed research plan - CO inhalation therapy exerts its beneficial effects on preclinical models of PAH by modulating the expression and interaction of caveolin-1 and endothelial nitric oxide synthase. This hypothesis will be tested by pursuing the following specific aims.
Specific Aim I : Establish the efficacy of inhaled CO on vascular remodeling and endothelial cell dysfunction in preclinical PAH.
Specific Aim II : Determine the role caveolin-1 in mediating the therapeutic effects of exogenous CO in experimental murine pulmonary hypertension.
Specific Aim III : Determine the role of eNOS derived NO in mediating the therapeutic effects of exogenous CO in experimental murine pulmonary hypertension. The proposed research plan is based on a foundation of strong preliminary data and is designed to reveal a mechanistic role for cav-1 and eNOS/NO in the therapeutic effects of inhaled CO in PAH. The importance of the proposed research is underscored by the poorly understood mechanisms of CO-induced cytoprotection in pulmonary arterial hypertension. Upon completion of the proposed research we will have a better foundation upon which to investigate the novel therapeutic use of inhaled CO in this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL085134-02S1
Application #
7842893
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$191,634
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bauer, Eileen M; Zheng, Han; Lotze, Michael T et al. (2014) Recombinant human interferon alpha 2b prevents and reverses experimental pulmonary hypertension. PLoS One 9:e96720
Bauer, Eileen M; Chanthaphavong, R Savanh; Sodhi, Chhinder P et al. (2014) Genetic deletion of toll-like receptor 4 on platelets attenuates experimental pulmonary hypertension. Circ Res 114:1596-600
Bauer, Eileen M; Shapiro, Richard; Billiar, Timothy R et al. (2013) High mobility group Box 1 inhibits human pulmonary artery endothelial cell migration via a Toll-like receptor 4- and interferon response factor 3-dependent mechanism(s). J Biol Chem 288:1365-73
Cruz, J Agustin; Bauer, Eileen M; Rodriguez, Andres I et al. (2012) Chronic hypoxia induces right heart failure in caveolin-1-/- mice. Am J Physiol Heart Circ Physiol 302:H2518-27
Bauer, Philip M; Bauer, Eileen M; Rogers, Natasha M et al. (2012) Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. Cardiovasc Res 93:682-93
Bauer, Eileen M; Zheng, Han; Comhair, Suzy et al. (2011) Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice. PLoS One 6:e28578
Gangopahyay, Archana; Oran, Max; Bauer, Eileen M et al. (2011) Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation. J Biol Chem 286:33134-40
Rodriguez, Andres I; Gangopadhyay, Archana; Kelley, Eric E et al. (2010) HO-1 and CO decrease platelet-derived growth factor-induced vascular smooth muscle cell migration via inhibition of Nox1. Arterioscler Thromb Vasc Biol 30:98-104
Zuckerbraun, Brian S; Shiva, Sruti; Ifedigbo, Emeka et al. (2010) Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 121:98-109
Cole, Marsha P; Rudolph, Tanja K; Khoo, Nicholas K H et al. (2009) Nitro-fatty acid inhibition of neointima formation after endoluminal vessel injury. Circ Res 105:965-72