Atherosclerosis is an inflammatory disease. Clinical studies show that elevated serum markers of inflammation predict an increased risk for atherosclerosis. Animal studies show that inflammatory mediators play a role in atherogenesis. Although pro-inflammatory pathways have been shown to increase atherosclerosis, the protective roles of anti-inflammatory pathways are less well studied. We and others have previously shown that nitric oxide (NO) inhibits vascular diseases. ApoE null mice that also lack the endothelial nitric oxide synthase (eNOS, or NOS3) gene have more severe atherosclerosis than ApoE mice that express NOS3. In humans, endothelial dysfunction (characterized by an inability to produce NO) is associated with coronary artery disease (CAD). Thus, NO may protect the vasculature from atherosclerosis. The molecular mechanisms by which NO inhibits atherosclerosis are unknown. However, we and others recently discovered that NOS decreases inflammation in transplant arteriosclerosis. In particular, we found that the inducible nitric oxide synthase (iNOS, or NOS2) inhibits the release of WeibeI-Palade bodies from endothelial cells in donor hearts. Since WeibeI-Palade bodies contain inflammatory and thrombotic mediators, inhibition of WeibeI-Palade body release may explain part of the anti-inflammatory effects of NO in transplant vasculopathy and other inflammatory vascular diseases, including atherosclerosis. We hypothesize that NO derived from NOS inhibits vascular inflammation, in part by inhibiting WeibeI-Palade body exocytosis. We now propose to explore the molecular mechanisms by which NO inhibits WeibeI-Palade body release. Preliminary Data show that NO blocks WeibeI-Palade body release from cultured endothelial cells. We will begin by determining the mechanisms by which WeibeI-Palade bodies are normally released. We will next define the molecules of the exocytosis machinery that are targets of NO. Finally, we will examine the role of reactive oxygen species in regulating WeibeI-Palade body exocytosis. These studies will characterize novel molecular mechanisms by which radicals regulate vascular inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL074061-04S1
Application #
7426027
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
2004-05-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$51,952
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101
Ferlito, Marcella; Fulton, William B; Zauher, Mohamed A et al. (2010) VAMP-1, VAMP-2, and syntaxin-4 regulate ANP release from cardiac myocytes. J Mol Cell Cardiol 49:791-800
Harris, Tamia A; Yamakuchi, Munekazu; Kondo, Maiko et al. (2010) Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol 30:1990-7
Lowenstein, Charles J; Cameron, Scott J (2010) High-density lipoprotein metabolism and endothelial function. Curr Opin Endocrinol Diabetes Obes 17:166-70
Jeong, Youngtae; Chaupin, Damian F; Matsushita, Kenji et al. (2009) Aldosterone activates endothelial exocytosis. Proc Natl Acad Sci U S A 106:3782-7
Yamakuchi, Munekazu; Ferlito, Marcella; Morrell, Craig N et al. (2008) Exocytosis of endothelial cells is regulated by N-ethylmaleimide-sensitive factor. Methods Mol Biol 440:203-15
Yamakuchi, Munekazu; Bao, Clare; Ferlito, Marcella et al. (2008) Epigallocatechin gallate inhibits endothelial exocytosis. Biol Chem 389:935-41
Yamakuchi, Munekazu; Ferlito, Marcella; Lowenstein, Charles J (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A 105:13421-6
Cao, Wangsen; Bao, Clare; Padalko, Elizaveta et al. (2008) Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 205:1491-503
Morrell, Craig N; Sun, Henry; Ikeda, Masahiro et al. (2008) Glutamate mediates platelet activation through the AMPA receptor. J Exp Med 205:575-84

Showing the most recent 10 out of 31 publications