The overall goal of this Program Project is to understand the clinical, cellular and molecular mechanisms that underlie arterial dysfunction, with a focus on the pathobiology of diabetic vasculopathy. This application is for the renewal of a Program Project Grant that has been funded continuously for 12 years. In this renewal application, as in the current Program, we propose a broad range of experimental approaches that range from molecular analyses to studies of human patients. Project 1 is entitled """"""""Insulin and receptor-modulated pathways of eNOS regulation"""""""" and is led by the Principal Investigator of this Program, Dr. Thomas Michel. The proposed studies build upon recent discoveries in Dr. Michel's laboratory on the insulin-modulated reversible nitrosation of eNOS and on recent findings on the differential roles of caveolin in insulin signaling. Project 2 is entitled """"""""KLF2, diabetes, and gene regulation in endothelial cells"""""""", and is led by Dr. Mukesh Jain, whose recent discoveries on the central role of the transcription factor KLF2 have provided important new insights into the coordinated control of endothelial gene expression in normal and diabetic states. Dr. Richard Lee leads Project 3, """"""""Thioredoxin and control of vascular redox state"""""""" explores the role of the newly-identified glucose-regulated protein Txnip (thioredoxin-interacting protein) in the regulation of the key redoxactive protein thioredoxin in vascular tissues. Dr. Jorge Plutzky's Project 4, """"""""Modulation of endogenous PPAR activation"""""""" extends his group's prior observations regarding endogenous PPAR ligands to explore his novel findings on endogenous pathways of PPAR antagonism. Project 5, led by Dr. Mark Creager, is entitled """"""""Mechanisms of arterial dysfunction in patients with type 2 diabetes mellitus"""""""" and will explore in these patients the role of insulin modulated nitric oxide signaling pathways in the control of vascular function, with a focus on the effects of free fatty acids, the mechanisms of insulin resistance, and the role of inflammation. An Administrative Core A (Dr. Michel) will provide budgetary, logistic and administrative support for the project leaders in this Program. Core B (Drs. Brian Hoffman and George King), """"""""Animal models of diabetes and arterial dysfunction"""""""" will provide support for the development and analysis of animal models relevant to study of diabetic arteriopathy. Core C (Dr. Peter Libby), """"""""Tissue Analyses"""""""", will perform immunohistochemical and lipid analyses. All the investigators in this Program have had longstanding scientific interactions, and together propose a broad range of complementary and synergistic experimental approaches to a fundamental problem in vascular disease.

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
Rabadan-Diehl, Cristina
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
Steinhorn, Benjamin; Sorrentino, Andrea; Badole, Sachin et al. (2018) Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction. Nat Commun 9:4044
Brown, Jonathan D; Feldman, Zachary B; Doherty, Sean P et al. (2018) BET bromodomain proteins regulate enhancer function during adipogenesis. Proc Natl Acad Sci U S A 115:2144-2149
Samokhin, Andriy O; Stephens, Thomas; Wertheim, Bradley M et al. (2018) NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med 10:
Pang, Paul; Abbott, Molly; Abdi, Malyun et al. (2018) Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function. Nephrol Dial Transplant 33:923-934
Steinhorn, Benjamin; Sartoretto, Juliano L; Sorrentino, Andrea et al. (2017) Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4. Free Radic Biol Med 113:16-25
Handy, Diane E; Loscalzo, Joseph (2017) Responses to reductive stress in the cardiovascular system. Free Radic Biol Med 109:114-124
Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I et al. (2016) Endophenotype Network Models: Common Core of Complex Diseases. Sci Rep 6:27414
Maron, Bradley A; Stephens, Thomas E; Farrell, Laurie A et al. (2016) Elevated pulmonary arterial and systemic plasma aldosterone levels associate with impaired cardiac reserve capacity during exercise in left ventricular systolic heart failure patients: A pilot study. J Heart Lung Transplant 35:342-351
Bertero, Thomas; Oldham, William M; Cottrill, Katherine A et al. (2016) Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 126:3313-35
Wang, Rui-Sheng; Loscalzo, Joseph (2016) Illuminating drug action by network integration of disease genes: a case study of myocardial infarction. Mol Biosyst 12:1653-66

Showing the most recent 10 out of 266 publications