This application represents a request for continued support of the Program Project Grant entitled "Arterial dysfunction: basic and clinical mechanisms", which has had continued NHLBI support since 1992. A unifying concept in this renewal application is the investigation of pathophysiological mechanisms of endothelial cell metabolism and oxidative stress that modify critical pathways in endothelial cells leading to arterial dysfunction. This research program unites the efforts of investigators working in basic and translational science laboratories at Brigham and Women's Hospital. Discoveries by the Project Leaders and by others in the field have led to the identification of the vascular endothelium as a key modulator of organismal metabolism, along with a growing understanding ofthe role of redox-modulated pathways in the control of vascular function. Oxidative stress represents a common feature of vascular disease states, yet the molecular mechanisms that modulate cellular redox balance in normal and diseased vascular tissues remain incompletely understood. The focus in this renewal application is on achieving a greater understanding of the pathophysiology of arterial dysfunction with a focus on endothelial cells as a gateway for metabolic control pathways that are dynamically modulated by redox pathways. The Project Leaders for this renewal application represent a cohort of experienced investigators in vascular biology. Project 1, "Redox regulation of eNOS signaling pathways in vascular endothelium", is led by T. Michel, who also directs the "Animal models of redox metabolism and vascular dysfunction" Core. Project 2, "The endothelial PPARy-RXR transcriptional complex in the control of metabolism", is led by J. Plutzky;R. Lee leads Project 3, "Thioredoxin-interacting protein in endothelial and organismal metabolism". J. Loscaizo leads Project 4, "Glutathione peroxidase-1, mitochondrial function, and endothelial phenotype", and also is Co-Director of the Redox Biochemistry Core, which is directed by V. Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman.

Public Health Relevance

Many cardiovascular diseases are characterized by oxidative stress pathways that lead to arterial dysfunction. The research projects in this Program Project Grant are led by experienced vascular biologists and biochemists who have identified a common experimental theme exploring the role of oxidative stress on pathways leading to vascular disease and to metabolic abnormalities.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Gao, Yunling
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Brown, Jonathan D; Lin, Charles Y; Duan, Qiong et al. (2014) NF-?B directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56:219-31
Lee, Samuel; Min Kim, Soo; Dotimas, James et al. (2014) Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress. EMBO Mol Med 6:732-43
Taqueti, Viviany R; Di Carli, Marcelo F; Jerosch-Herold, Michael et al. (2014) Increased microvascularization and vessel permeability associate with active inflammation in human atheromata. Circ Cardiovasc Imaging 7:920-9
Zhao, Yuzheng; Yang, Yi; Loscalzo, Joseph (2014) Real-time assessment of the metabolic profile of living cells with genetically encoded NADH sensors. Methods Enzymol 542:349-67
Chatzizisis, Yiannis S; Blankstein, Ron; Libby, Peter (2014) Inflammation goes with the flow: implications for non-invasive identification of high-risk plaque. Atherosclerosis 234:476-8
Barroso, Madalena; Florindo, Cristina; Kalwa, Hermann et al. (2014) Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression. J Biol Chem 289:15350-62
Nallamshetty, Shriram; Le, Phuong T; Wang, Hong et al. (2014) Retinaldehyde dehydrogenase 1 deficiency inhibits PPAR?-mediated bone loss and marrow adiposity. Bone 67:281-91
Folco, Eduardo J; Sukhova, Galina K; Quillard, Thibaut et al. (2014) Moderate hypoxia potentiates interleukin-1? production in activated human macrophages. Circ Res 115:875-83
Kalwa, Hermann; Sartoretto, Juliano L; Martinelli, Roberta et al. (2014) Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium. Proc Natl Acad Sci U S A 111:3383-8
Shiroto, Takashi; Romero, Natalia; Sugiyama, Toru et al. (2014) Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium. PLoS One 9:e87871

Showing the most recent 10 out of 197 publications