Project 5 represents a continuation of a highly productive program initiated as part of the original Program project in Vascular Biology and Medicine. A key focus of the work pursued under this grant related to the effects of lipid lowering on vascular function. Notably, the Vascular Medicine and Biology Program Project supported seminal work demonstrating an improvement in coronary vasodilatation in response to the endothelial-dependent vasodilator acetylcholine when patients underwent lipid lowering and/or antioxidant treatment, published in The new England Journal of Medicine. The current project will embark in new directions. First, the role of endothelin in unstable and stable coronary lesions will be proved. These studies will test the hypothesis that endothelin-mediated vasoconstriction plays a role in flow impairment in the acute coronary syndromes. These studies will involve selective inhibitors of endothelial A or B type receptors. Studies from Dr. Libby's laboratory and others have documented altered endothelin gene expression in atheroma. This aspect will be pursued, in conjunction with the Vascular pathology Core, in atherectomy specimens. Further studies will test the hypothesis that coronary risk factors (e.g. hypercholesterolemia) change basal vascular tone in an endothelin-dependent manner. Another aim of this project will test the role of endothelin in pulmonary hypertension, primary, secondary, and hypoxia-induced. This project will involve observations on adult patient, and in conjunction with the Boston Adult Congenital Heart Disease Service shared between the Cardiovascular Division of the Brigham and Women's Hospital and Children's Hospital medical Center, younger-age patients will be included in the studies as appropriate. Once more, the Vascular pathology Core laboratory will aid in the analysis of biopsy specimens obtained from patients with pulmonary hypertension. In a third specific aim, the role of endothelin in vasomotor alterations associated with various cardiac risk factors will be explored, using the selective endothelin antagonist and the peripheral circulation probed by forearm studies. These latter studies will utilize the expertise of Dr. Creager, the project leader of Project 4.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048743-11
Application #
6654177
Study Section
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
11
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Garmaroudi, Farshid S; Handy, Diane E; Liu, Yang-Yu et al. (2016) Systems Pharmacology and Rational Polypharmacy: Nitric Oxide-Cyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case. PLoS Comput Biol 12:e1004822
Keating, Samuel T; Plutzky, Jorge; El-Osta, Assam (2016) Epigenetic Changes in Diabetes and Cardiovascular Risk. Circ Res 118:1706-22
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

Showing the most recent 10 out of 266 publications