Kimberly Dunham-Snary, Queen’s University

Supervisor: Stephen Archer, Queen’s University

Cardiopulmonary diseases are the leading cause of death in Canada. Pulmonary hypertension (PH) is divided into 5 groups. Group 1 is a rare form of PH affecting the lung vasculature in the absence of other cardiopulmonary diseases; all approved PH therapies are restricted to Group 1 PH patients. However, Group 3 PH (related to chronic hypoxia and/or lung diseases) afflicts hundreds of thousands of Canadians. While PH is a negative prognostic factor in patients with lung disease or hypoxia there is no known therapy for Group 3 PH. This project focuses on unifying the mechanism of hypoxic pulmonary vasoconstriction (HPV) and the pathology of PH. HPV is the process by which ventilation-perfusion matching is achieved during hypoxia via the constriction of resistance arteries within the lung vasculature (nearly all other blood vessels dilate during hypoxia). The HPV response is dramatically reduced in a number of pathologies, including pulmonary arterial hypertension (PAH). Prior work from our lab identified mitochondria in pulmonary artery smooth muscle cells (PASMC) as the major oxygen sensor that triggers HPV. The mitochondrial network in PASMC is unique in that it alters production of diffusible redox mediators, including reactive oxygen species (ROS) in proportion to partial pressure of oxygen (PO2). These ROS (including hydrogen peroxide, H2O2) are produced within the mitochondrial electron transport chain (ETC). We propose that mitochondrial-derived H2O2 serves as a diffusible redox-signaling molecule that reflects alveolar PO2, and regulates pulmonary vascular tone via its interaction with redox-sensitive ion channels and enzymes. The opposing effects of hypoxia on PA and renal arteries (RA) (constriction vs. vasodilatation) are mimicked by inhibitors of ETC Complex I (rotenone) and III (antimycin A), implicating these complexes as the source of the oxygen-sensitive ROS signal.

Hypothesis: One or more subunits of mitochondrial ETC Complex I serve as the mitochondrial redox oxygen sensor, and these subunit(s) are downregulated in PAH.

Goals: We will determine differences in production of mitochondrial hydrogen peroxide (the putative mediator of the oxygen sensing signaling cascade) in pulmonary vs. renal SMC as well as variation in mitochondrial function, metabolism and gene expression. Subsequently, we will translate these results and perform targeted screening of PASMC from PAH patients compared to healthy controls. Finally, we will explore the effects of silencing candidate subunit(s) in healthy human PASMC and rat PASMC, in an effort to confirm the molecular identity of the mitochondrial proteins required for oxygen sensing.

Relevance: Better understanding of HPV will identify new potential therapeutic targets and advance the creation of new therapies for patients with PH. Elucidation all aspects of the oxygen sensing system is critical to combat diseases of impaired oxygen sensing and to devise new therapies for populations at altitude, in whom excessive HPV can cause diseases including high altitude pulmonary edema (HAPE). This proposal relates to CVN’s Priority Research Areas (Identifying targets for early detection strategies for populations at high risk for vascular diseases) as well as the overall goal of CVN (to improve the health of Canadians by furthering the field of vascular research).