Right ventricular failure is the leading cause of death in patients with severe pulmonary arterial hypertension. While It is known that right heart failure represents a major co-morbidity in advanced lung disease, little is known about right ventricular adaptation and failure within the context of secondary pulmonary hypertension. Interaction between the heart and pulmonary circulation plays an important role in pulmonary vascular stiffening and increased tone thus conferring additional hemodynamic stress on the RV. The initial response of both the pulmonary vasculature and the heart to hemodynamic and neurohormonal stress is hypertrophy. Numerous studies on the /e/i^ ventricle have concluded that hypertrophy often progresses to cardiac dysfunction and maladaptive remodeling culminating in heart failure. Similar events are proposed for the right heart. Currently, we lack an understanding of the fundamental relationship between hypertrophy and failure in the RV as well as the interaction between the heart and lung vasculature, particularly in the setting of secondary PAH. We postulate that common stress pathways in the heart and pulmonary circulation promote increased vascular resistance/remodeling and RV hypertrophy/failure. Consistent with this thesis, preliminary data suggest that increased reactive oxygen species (ROS) signaling and NO synthase uncoupling in both the RV and pulmonary vasculature represent a central pathological stress response in chronic hypoxia and cigarette smoke exposure. Secondary reduction in NO bioavailability in the RV, caused by eNOS dimer formation and increases in pathological eNOS derived ROS/superoxide anion (Oz')-generation is associated with the development of contractile dysfunction and maladaptive remodeling. Preliminary data implicate upstream NADPH oxidase activation in NOS uncoupling. Thus it is hypothesized that a convergent stress response involving ROS generation and eNOS uncoupling drives reduced NOcGMP signaling to produce maladaptive right ventricular and pulmonary vascular remodeling during hemodynamic and/or neurohormonal stress. The following aims will test this hypothesis: (1) determine the role of eNOS uncoupling as a common mechanism in the development of pulmonary vascular and right ventricular maladaptive remodeling;(2) investigate the 'kindling'role of NADPH oxidase (Nox)-derived ROS in eNOS dysfunction promoting feed-fonward ROS generation that leads to vascular and RV maladaptive remodeling;(3) develop and test small molecule inhibitors targeting pathological ROS signaling to prevent RV failure in murine and primate models of PAH.

Public Health Relevance

The proposed studies will add greatly to our basic understanding of cardiopulmonary disease. It is expected that the present proposal will result in new therapeutics to directly target the mechanistic pathways involved in the remodeling of the pulmonary vasculature and right ventricle in conditions of pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
Kanias, Tamir; Sinchar, Derek; Osei-Hwedieh, David et al. (2016) Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease. Transfusion 56:2571-2583
Procter, Nathan Ek; Ball, Jocasta; Ngo, Doan Tm et al. (2016) Gender and tachycardia: independent modulation of platelet reactivity in patients with atrial fibrillation. J Geriatr Cardiol 13:202-8
Vanderpool, Rebecca R; Rischard, Franz; Naeije, Robert et al. (2016) Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved? Int J Cardiol 223:93-94
Maron, Bradley A; Gladwin, Mark T; Simon, Marc A (2016) Update in Pulmonary Vascular Disease 2015. Am J Respir Crit Care Med 193:1337-44
Gladwin, Mark T (2016) Cardiovascular complications and risk of death in sickle-cell disease. Lancet 387:2565-74
Ambrozova, Gabriela; Martiskova, Hana; Koudelka, Adolf et al. (2016) Nitro-oleic acid modulates classical and regulatory activation of macrophages and their involvement in pro-fibrotic responses. Free Radic Biol Med 90:252-60
Al Ghouleh, Imad; Meijles, Daniel N; Mutchler, Stephanie et al. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci U S A 113:E5308-17
Azarov, Ivan; Wang, Ling; Rose, Jason J et al. (2016) Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med 8:368ra173
Meijles, Daniel N; Pagano, Patrick J (2016) Nox and Inflammation in the Vascular Adventitia. Hypertension 67:14-9
Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana et al. (2016) Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition. Biochim Biophys Acta 1860:2428-37

Showing the most recent 10 out of 132 publications