(Verbatim from the application): Premature cardiovascular disease is a major cause of mortality in systemic lupus erythematosus (SLE) with the risk of myocardial infarction increased up to 50-fold. The mechanisms underlying accelerated atherosclerosis in SLE are poorly understood. Recent studies indicate that inflammation, through the effects of inflammatory cytokines, and oxidative stress, through lipid peroxidation, play important roles in the pathogenesis of atherosclerosis. We postulate that accelerated, inflammation-promoted atherosclerosis occurs in SLE through these mechanisms. Thus, we propose to test the hypotheses: 1) that structural and functional vascular damage is more frequent and more severe in patients with SLE than matched controls and 2) that this impairment of vascular integrity is associated with clinical and laboratory markers of inflammation, plasma homocysteine concentrations, and oxidative stress. Endothelium-dependent, flow-mediated dilation of the brachial artery measured by ultrasound, and coronary calcium volume measured by electron beam computed tomography (EBCT) will provide functional and structural measures of vascular integrity, respectively. The pathogenesis of atherosclerosis and inflammation have strong genetic components. We will examine the role of such genetic factors focusing initially on nitric oxide (NO), a mediator that affects both structural and functional vascular integrity, and test the hypothesis 3) that polymorphism of the endothelial nitric oxide synthase gene is associated with vascular damage in SLE. Of great interest are recent studies showing that HMG coenzyme-A reductase inhibitors (statin lipid lowering drugs) can reverse vascular damage, through both lipid lowering and lipid-independent mechanisms. We will examine the hypothesis 4) that vascular damage in SLE is reversible by treatment with a statin drug. The proposed studies will provide a basic understanding of the interrelationship between inflammation, oxidative stress, genetic polymorphism, and vascular damage, and will suggest strategies for reversing or preventing such damage in SLE and, potentially, other diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065082-01A1
Application #
6334148
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Goldman, Stephen
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$333,153
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Solus, Joseph F; Chung, Cecilia P; Oeser, Annette et al. (2015) Genetics of serum concentration of IL-6 and TNF? in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis. Clin Rheumatol 34:1375-82
Bradham, William S; Ormseth, Michelle J; Oeser, Annette et al. (2014) Insulin resistance is associated with increased concentrations of NT-proBNP in rheumatoid arthritis: IL-6 as a potential mediator. Inflammation 37:801-8
Kawai, Vivian K; Avalos, Ingrid; Oeser, Annette et al. (2014) Suboptimal inhibition of platelet cyclooxygenase 1 by aspirin in systemic lupus erythematosus: association with metabolic syndrome. Arthritis Care Res (Hoboken) 66:285-92
Manavathongchai, Siriporn; Bian, Aihua; Rho, Young Hee et al. (2013) Inflammation and hypertension in rheumatoid arthritis. J Rheumatol 40:1806-11
Ormseth, M J; Swift, L L; Fazio, S et al. (2013) Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus. Lupus 22:26-33
Lipson, Aliza; Alexopoulos, Nikolaos; Hartlage, Gregory Randell et al. (2012) Epicardial adipose tissue is increased in patients with systemic lupus erythematosus. Atherosclerosis 223:389-93
Bradham, William S; Bian, Aihua; Oeser, Annette et al. (2012) High-sensitivity cardiac troponin-I is elevated in patients with rheumatoid arthritis, independent of cardiovascular risk factors and inflammation. PLoS One 7:e38930
Lertnawapan, R; Bian, A; Rho, Y H et al. (2012) Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus. Lupus 21:279-87
Rho, Young Hee; Solus, Joseph; Raggi, Paolo et al. (2011) Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 63:535-41
Kawai, V K; Solus, J F; Oeser, A et al. (2011) Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus. Lupus 20:1526-34

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