Pulmonary Hypertension (PH) is characterized by increased pulmonary vascular resistance, pulmonary vascular remodeling, and increases in blood pressure that often results in right ventricular hypertrophy. These vascular changes can ultimately result in right heart failure. Current evidence suggests that reactive oxygen species (ROS) generated by both mitochondrial respiration and NADPH oxidase activity may play a role in vascular cell proliferation, right ventricular hypertrophy, and PH pathogenesis. The present study examines the role of crosstalk between mitochondria-derived ROS and ROS generated via NADPH oxidase activity in the development of hypoxia-induced PH. NADPH Oxidases (Noxes) are implicated in the generation of cellular ROS generation in the believed to promote PH pathogenesis by increasing proliferation. Some studies have also implicated mitochondrial ROS as contributing to endothelial cell dysfunction mediated by disregulated redox balance within the cell. Though the mechanism(s) underlying the development/progression of PH remain incompletely defined, we hypothesize that hypoxia exposure increases ROS generation and this occurs as the result of crosstalk between ROS generated by the mitochondria and Noxes which have deferential effects on the cells of the pulmonary vasculature. These ROS compartments impact hypoxia-induced proliferation by differentially affecting expression of NADPH oxidase, proliferation genes, and apoptotic signaling markers and thereby differentially regulate vascular remodeling and possibly pulmonary hypertension. We believe that modulation of the expression or activity of NADPH oxidase family members will provide a novel mechanism to specifically target ROS generation, preventing endothelial dysfunction and preventing pulmonary hypertension. This proposal therefore involves two specific aims: 1) To explore the role of crosstalk between ROS sources in hypoxia-induced alterations in endothelial proliferation, ROS generation, and apoptosis (Aim 1), and 2) to determine the role of crosstalk between mitochondria-derived ROS and Nox4 in hypoxia-induced pulmonary hypertension novel murine models (Aim 2).
These aims will be accomplished through both molecular and pharmacological experimentation under the guidance of Dr. Roy L. Sutliff and Dr. C. Michael Hart. These results aim to clearly address the molecular mechanism leading to and aiding PH pathology. This NRSA grant funding, along with assistance from my established mentors, and the several training opportunities available at Emory University, this pre-doctoral training will be used to expand my knowledge of research techniques, experimental design, and manuscript writing. This award will prepare me for my long-term goal of becoming an independent academic researcher.
Pulmonary hypertension (PH) is a progressive disorder accompanied by significant morbidity and mortality. Current treatments target symptoms without adequately addressing the underlying mechanisms that promote endothelial and vascular smooth muscle dysregulation and proliferation. Our goal is to examine the role of crosstalk between mitochondria-derived ROS and ROS generated via NADPH oxidase activity in development of hypoxia-induced PH.
|Liu, Peng; Feng, Tingting; Zuo, Xuan et al. (2018) A novel SIRT1 activator E6155 improves insulin sensitivity in type 2 diabetic KKAy mice. Biochem Biophys Res Commun 498:633-639|
|Adesina, Sherry E; Kang, Bum-Yong; Bijli, Kaiser M et al. (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med 87:36-47|