Right ventricular (RV) failure is the leading cause of death in patients with pulmonary arterial hypertension (PAH). Hypoxia-induced PAH is a common form of the disease leading to heart failure. A poor understanding of pathologic mechanisms presents a barrier to clinical approaches targeting the disease, which is often associated with rapid and aggressive vascular remodeling, plexiform lesion (PL) formation, and RV failure. Reactive oxygen species (ROS) from NADPH oxidases (Noxs) are implicated in PAH and previous data support a role for Nox2 in pulmonary vascular endothelial (EC) proliferation. However, despite its expression in the pulmonary vascular wall, no information exists for Nox1 in PAH. Importantly, a functional role for Nox1 in vascular wall thickening and PL formation is entirely unknown. We propose a novel role for Nox1 in promoting proliferation and vascular remodeling via Gremlin1, an antagonist of bone morphogenetic protein. This hypothesis is based on a recent association of Gremlin1 with PAH and our preliminary data supporting Nox1-mediated Gremlin1 expression in human pulmonary artery endothelial cell (HPAEC) proliferation. In fact, the role that any Nox plays in mediating upstream and downstream mediators of EC Gremlin1, including sonic hedgehog and CREB, is entirely unknown. Our previous aims led to development of a highly-selective and efficacious Nox1 inhibitor. This inhibitor, as well as other molecular genetic techniques, allows identification of multiple new pathways involving Gremlin1 in hypoxia-induced PAH. We will test the central hypothesis that Nox1 propagates Gremlin1-mediated signaling, thereby promoting hypoxia- induced PAH and RV failure. This will be tested by addressing the following aims: (1) To interrogate the expression of Nox1 and its contribution to ROS production and Gremlin1- mediated signaling in human pulmonary endothelial cell proliferation under hypoxic conditions; (2) To determine whether specific Nox1 inhibitor permeates and targets hypoxia-induced endothelial ROS signaling and Gremlin1 expression and attenuates hemodynamics in a mouse model of PAH; and (3) To determine whether aerosolization of Nox1 inhibitor prevents and/or reverses RV failure in a rat model of vascular occlusive PAH. This paradigm-shifting proposal uncovers a novel role for Gremlin1-Nox1 in PAH and RV failure. The research plan, built on compelling preliminary data, is expected to open up a new field of inquiry in vascular biology and is conceptually and technologically innovative. From a therapeutic standpoint, delivery of a novel and highly-specific Nox1 inhibitor to disrupt this pathway in the pulmonary vascular endothelium via aerosolization is expected to serve as a firm foundation for new drug therapies.
Right ventricular (RV) failure is the leading cause of death in patients with pulmonary hypertension (PH). RV failure is a consequence of increased pulmonary arterial resistance due to thickening and occlusion of pulmonary vessels. Despite approved therapies to treat PH, RV failure contributes to greater than 50% of deaths in this disease. This project aims to open a new field of inquiry by (a) identifying novel pathways involving pulmonary vascular oxidant production leading to vascular thickening and occlusion; and (b) testing promising therapies aimed at abolishing these pathways and alleviating PH and RV failure.
|Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:|
|Csányi, Gábor; Feck, Douglas M; Ghoshal, Pushpankur et al. (2017) CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxid Redox Signal 26:886-901|
|Li, Yao; Pagano, Patrick J (2017) Microvascular NADPH oxidase in health and disease. Free Radic Biol Med 109:33-47|
|Ghouleh, Imad Al; Sahoo, Sanghamitra; Meijles, Daniel N et al. (2017) Endothelial Nox1 oxidase assembly in human pulmonary arterial hypertension; driver of Gremlin1-mediated proliferation. Clin Sci (Lond) 131:2019-2035|
|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|
|Sahoo, Sanghamitra; Meijles, Daniel N; Al Ghouleh, Imad et al. (2016) MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension. PLoS One 11:e0153780|
|Meijles, Daniel N; Pagano, Patrick J (2016) Nox and Inflammation in the Vascular Adventitia. Hypertension 67:14-9|
|Sahoo, Sanghamitra; Meijles, Daniel N; Pagano, Patrick J (2016) NADPH oxidases: key modulators in aging and age-related cardiovascular diseases? Clin Sci (Lond) 130:317-35|
|Quesada, I M; Lucero, A; Amaya, C et al. (2015) Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques. Atherosclerosis 242:469-75|
|Mukawera, Espérance; Chartier, Stefany; Williams, Virginie et al. (2015) Redox-modulating agents target NOX2-dependent IKK? oncogenic kinase expression and proliferation in human breast cancer cell lines. Redox Biol 6:9-18|
Showing the most recent 10 out of 41 publications