The Pathobiological Role of Dysregulated Pulmonary Vascular Metabolism in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension
Abstract
Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) is a fatal complication of systemic sclerosis, characterized by proliferation and narrowing of arteries in the lungs (pulmonary arteries), and subsequent elevation of pulmonary arterial pressure. As a result of contracting against this high pressure, the right-sided chamber of the heart, or the right ventricle, gradually becomes dysfunctional. Despite the recent introduction of newer therapies, more than half of SScPAH patients die from right ventricular failure within 5 years of diagnosis. This progressive, incurable disease affects approximately 10% of systemic sclerosis patients, many in their fourth and fifth decades of life. We believe the difficulty treating patients with SScPAH represents the currently incomplete understanding of how SScPAH arises and mechanisms that promote disease progression. One biological process that appears to be altered and significantly contributing to SScPAH is metabolism of the pulmonary arteries, for example, ways in which the cells that comprise the blood vessels utilize glucose and fatty acids. Although a large aggregate of compelling data suggests that pulmonary vascular metabolism has a significant role in SScPAH, targeting metabolism has not been established as a reliable means to manage the disease. This hindrance to clinical application of metabolism-altering therapies reflects methodologic limitations of traditional experimental approaches that preclude full understanding of how pulmonary vascular metabolism promotes SScPAH. We propose to overcome these barriers by applying two novel investigational tools. We plan to quantify metabolic activities of the pulmonary arteries in SScPAH using two distinct and complementary approaches: (1) assessing the degree to which genes encoding metabolism-related proteins are utilized by pulmonary arteries in explanted SScPAH lung tissues; and (2) obtaining blood samples from exercising SScPAH patients, then measuring uptake or excretion of various metabolites specifically by the pulmonary blood vessels, at rest and during three stages of standardized exercise. These research methodologies, which have not been previously utilized to study SScPAH or systemic sclerosis in general, have following major advantages and therefore support a potential large impact of our research: - Simultaneous quantification of all relevant metabolic pathways, which interact and feedback with each other, at both genetic and metabolite levels, rather than only probing one or few targets at a time. - Assessment of the entire set of ~19,000 protein-coding genes (transcripts) in pulmonary arteries, including those associated with metabolism, directly on lung tissues, thereby allowing linkage of gene transcriptions to individual pulmonary vascular lesions and preserving anatomic information. - Isolated examination of pulmonary vascular metabolic activity in alive, exercising SScPAH patients, assessed at three stages of exercise previously shown to have clinical and prognostic significance: pre-exercise free-wheeling, peak exercise, and recovery. Our study design involves two sites of blood draw, the pulmonary artery (neck) and the systemic radial artery (wrist); taking the difference between the two concentrations allows quantification of net uptake or excretion of that particular metabolite by the pulmonary vascular bed. We anticipate performing, for the first time, detailed metabolic characterization of the SScPAH pulmonary vasculature in the context of anatomic and physiologic parameters, and identifying metabolic targets responsible for disease initiation and persistence. We propose to fulfill three Idea Development Award Focus Areas: (1) using clinical samples, define the functional role of dysregulated metabolism in propagating SScPAH; (2) define metabolites and metabolic pathways that help predict morbidity and exercise tolerance; and (3) utilize transcriptomics and metabolomic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210457
Entities
People
- Michael D Lee
Organizations
- United States Army
- University of California, San Francisco