The overall goal of this application is to determine the mechanisms by which vascular inflammation impairs vasodilation. Recent reports from this laboratory demonstrate that an apoA-l mimetic, 4F, dramatically improves endothelium-and eNOS-dependent vasodilation in two distinct murine models of vascular disease-hypercholesterolemia and sickle cell disease (SCD). On the basis that apoA-l mimetics were designed to improve HDL function, we hypothesize that oxidative stress and inflammation induce HDL dysfunction, which in turn impairs vasodilation. In this application, we will test this hypothesis in a disease state and a murine model whose vascular dysfunction is more closely associated with inflammation than hyperlipidemia, sickle cell disease (SCD). Although SCD is primarily a genetic disease, many consider the chronic state of inflammation to play a role in the mechanisms by which SCD impairs vasodilation. This application investigates the concept that inflammation plays a central role in impairing vascular dysfunction by determining how the sickling red cell raises up new """"""""partner in crime"""""""" to induce vascular disease. The objectives of this application are to determine the interactions between inflammation, HDL function and proinflammatory lipids in hopes of identifying other down-stream """"""""partner(s)"""""""" who team up with the sickling red cell to impair vasodilation. We will investigate the role of acute phase proteins, proinflammatory HDL, proinflammatory lipids and xanthine oxidase on vascular function in transgenic SCD mice. Bioassays of plasma from severe and non-severe SCD patients and control subjects will be used to identify and rank potential partners that impair vasodilation and shift the balance of nitric oxide (-NO) and superoxide anion (O2.-) generation in the vessel wall. Mechanisms will be investigated at the vascular level to determine how SCD induces endothelial cell dysfunction. Hematopoietic stem cell transplantation (HSCT) of SCD into genetically engineered mice will be used to test alternative hypotheses that low-density lipoprotein contributes to impaired vasodilation in SCD. HSCT of SCD into an apoA-l knockout mouse that expresses apoA-l-deficient HDL will be used to test the alternative hypothesis that D-4F does not improve HDL function to restore vasodilation. The utility of D-4F in improving outcomes will be tested at the level of survival, mechanisms of ischemic injury, organ pathobiology and proteomics of HDL interactions with other inflammatory mediators. On the basis that D-4F improves vasodilation in other systems, our data suggest that targeting HDL may be an effective means of protecting vascular function in diseases characterized by chronic states of inflammation. Through these studies, new treatment modalities may be realized for preventing vascular dysfunction in a variety of diseases characterized by increases in oxidative stress and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081139-05
Application #
7798573
Study Section
Special Emphasis Panel (ZRG1-CVS-A (05))
Program Officer
Liu, Lijuan
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$367,766
Indirect Cost
Name
Medical College of Wisconsin
Department
Surgery
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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