Mast cells are known to be involved in vascular inflammation and atherosclerosis. Increasing evidence also suggests a role for infectious agents in initiating atherogenic events in the vessel wall. Our preliminary results show that histamine and tryptase, two major products of the mast cell, enhances endothelial cell (EC) inflammatory responses to Gram-positive and Gram-negative bacterial cell wall components presumably via upregulation of Toll-like receptor-2 and -4 (TLR2 and TLR4). The long-term objective of this grant application is to delineate the mechanism by which mast cell-derived histamine and tryptase act in synergy with the TLR ligands to amplify vascular inflammation and participate in the progression of atherosclerosis.
The specific aims of this project are: 1) Determine whether histamine and tryptase regulate the expression and function of TLR2 and TLR4 in normal human coronary artery endothelial cells (HCAEC). 2) Determine whether histamine-and tryptase-primed normal HCAEC and endothelial cells isolated from human atherosclerotic vessels are phenotypically similar and hyperresponsive to TLR2 and TLR4 ligands. 3) Determine whether histidine decarboxylase knockout mice (HOC-/-) and mast cell-deficient (Sl/SId) mice have decreased endothelial expression of TLR2 and TLR4 and are hyporesponsive to Gram-negative and Gram-positive bacterial PAMPs in vivo and in vitro. 4) Determine whether mast cell degranulation will accelerate the progression of atherosclerosis in an apoE-/- mice infected with C. pneumoniae, and evaluate whether changes in atherosclerotic lesions correlate with the endothelial expression of TLR2 andTLR4. The study will utilize real-time PCR, immunofluorescence and Western blot analyses, flow cytometry, confocal microscopy, and ELISA techniques, as applicable. Upon completion, the proposed studies will reveal the mechanism by which histamine and tryptase upregulate infection-associated vascular inflammation and will enhance our understanding of the role of mast cells in the pathogenesis of atherosclerosis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070101-02
Application #
7171603
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Wassef, Momtaz K
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$356,843
Indirect Cost
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Krystel-Whittemore, Melissa; Dileepan, Kottarappat N; Wood, John G (2015) Mast Cell: A Multi-Functional Master Cell. Front Immunol 6:620
Barua, Rajat S; Sharma, Mukut; Dileepan, Kottarappat N (2015) Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis. Front Immunol 6:572
Raveendran, Vineesh V; Smith, Donald D; Tan, Xiaoyu et al. (2014) Chronic ingestion of H1-antihistamines increase progression of atherosclerosis in apolipoprotein E-/- mice. PLoS One 9:e102165
Raveendran, Vineesh V; Kassel, Karen M; Smith, Donald D et al. (2014) H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice. Am J Physiol Gastrointest Liver Physiol 307:G219-28
Walia, Damandeep S; Sharma, Mukut; Raveendran, Vineesh V et al. (2012) Human mast cells (HMC-1 5C6) enhance interleukin-6 production by quiescent and lipopolysaccharide-stimulated human coronary artery endothelial cells. Mediators Inflamm 2012:274347
Smith, Donald D; Tan, Xiaoyu; Raveendran, Vineesh V et al. (2012) Mast cell deficiency attenuates progression of atherosclerosis and hepatic steatosis in apolipoprotein E-null mice. Am J Physiol Heart Circ Physiol 302:H2612-21
Raveendran, Vineesh V; Tan, Xiaoyu; Sweeney, Matthew E et al. (2011) Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. Immunology 132:578-88
Tan, X; Poulose, E M; Raveendran, V V et al. (2011) Regulation of the expression of cyclooxygenases and production of prostaglandin I? and E? in human coronary artery endothelial cells by curcumin. J Physiol Pharmacol 62:21-8
Smith, D D; Tan, X; Tawfik, O et al. (2010) Increased aortic atherosclerotic plaque development in female apolipoprotein E-null mice is associated with elevated thromboxane A2 and decreased prostacyclin production. J Physiol Pharmacol 61:309-16
Tan, Xiaoyu; Essengue, Suzanne; Talreja, Jaya et al. (2007) Histamine directly and synergistically with lipopolysaccharide stimulates cyclooxygenase-2 expression and prostaglandin I(2) and E(2) production in human coronary artery endothelial cells. J Immunol 179:7899-906

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