PPG - Endothelial Metabolism & Redox Imbalance in Vascular Disease
Program Director: Dr. Tohru Fukai
Co-Director: Dr. Masuko Ushio-Fukai
Institution: Vascular Biology Center, Medical College of Georgia at Augusta University
Overall
Redox imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS) (high ROS and low nitric oxide) is a fundamental mechanism of endothelial cell (EC) dysfunction contributing to the vascular inflammatory and metabolic diseases such as atherosclerosis, diabetes, and peripheral arterial disease. Evidence suggests that EC metabolism and ROS are intimately connected and involved in vascular disease. The current studies will identify key mechanisms dictating the interplay of metabolism with ROS/NO and how this impacts endothelial function, which will lead to new therapeutic strategies.
Jump to: Intended ImpactCentral Overall HypothesisSynergy & Integration OverallProjectsCores
Intended impact
We propose three highly integrated projects that will focus on the diverse mechanisms by which vascular risk factors perturb key ROS/metabolic pathways to promote vascular disease.
Central Overall Hypothesis
Imbalance between changes in EC metabolism and ROS/RNS (redox balance), induced by various risk factors, drives EC dysfunction and the development of vascular disease
Synergy & Integration Overall
Addressing the interplay between endothelial metabolism and oxidative stress is complex and involves multiple interrelated systems and thus is an ideal match for the enhanced scope of a program project.
We will investigate the key pathways unique to each project using different mouse models and cell-based approaches through the sharing of mice, tissues, and reagents and coordinated services across the 2 scientific cores.
Our highly accomplished experimental team has an established track record of interactions, productivity, and collaborations in the area of endothelial biology, ROS/NO, and EC metabolism.
Projects
Program Directors: Dr. Tohru Fukai (Contact PD/PI) who has expertise in oxidative stress and vascular disease and Dr. Masuko Ushio-Fukai (PD/PI) who has expertise in redox signaling and endothelial cell (EC) biology
Project—1
Project—2
Project—3
Role of Cu Transporter in EC Metabolism, ROS, & Atherosclerosis
Hypothesis: ATP7A dysfunction in inflamed endothelial cells disrupts copper (Cu) metabolism, causing intracellular Cu accumulation that promotes endothelial-to-mesenchymal transition (EndMT) through PFKFB3-driven glycolysis and mitoROS-mediated activation of TGF-β signaling.
The figure describes how the disturbed Cu metabolism induced by risk factors promotes endothelial dysfunction (EndMT) via excess ROS and glycolysis, driving atherosclerosis.
Sex & Leptin control of endothelial cell glycolysis & redox balance in Type 1 diabetes
Hypothesis: Endothelial cell (EC) metabolism regulates endothelial function in type 1 diabetes through sex-specific, leptin-dependent mechanisms involving PFKFB3- driven glycolysis & NOX1-mediated oxidative stress.
The figure shows that Type 1 Diabetes, through reduction in leptin and male and female sex steroid hormones, promotes endothelial dysfunction and vascular disease via redox imbalance and impaired endothelial cell glycolysis.
Mitochondrial dynamics protein Drp1 regulation of endothelial metabolism, ROS, & ischemic vascular disease
Hypothesis: VEGF/NOX-derived H₂O₂ regulates endothelial metabolism and angiogenesis through Drp1-mediated mitochondrial fission and AMPK/PFKFB3-driven glycolysis, but in diabetes, this pathway becomes dysregulated.
The figure shows Mitochondrial Drp1 integrates redox signaling with glycolysis through cysteine oxidation-mediated AMPK/PFKFB3 activation, driving angiogenesis, which is impaired in diabetes, leading to PAD.
Cores
Core A —Administrative Core
Core A will coordinate & oversee the research efforts of the individual projects to maximize project synergy and ensure administrative and regulatory compliance.
Core B — Animal & Metabolic Phenotype Analytic Core
This core will provide support for all projects with novel knockout or transgenic mice with endothelial gene alterations and in vivo metabolic measurements.
Core C — Endothelial Cell Analytic Core
This core will assist with isolation and characterization of primary endothelial cells from genetically modified mice and rigorous viral, CRIPSR/Cas9-mediated genetic manipulation of endothelial cells.