Atherosclerosis in animal models and in humans is associated with inflammation. Therapies that increase nitric oxide bioactivity reduce synthesis of proinflammatory proteins within the vessel wall by inhibiting transcriptional activation of target genes. As estrogen and lipid-lowering therapies have been shown to improve nitric oxide bioactivity, we administered conjugated equine estrogen .625 mg, simvastatin 10 mg or the combination daily for 6 weeks to 28 hypercholesterolemic (low density lipoprotein = 163+/-36 mg/dL; SD) postmenopausal women in a randomized, double blind, double-crossover study. We measured brachial artery flow-mediated dilation following forearm ischemia, and inflammatory cell adhesion molecules E-selectin, intercellular adhesion molecule (ICAM-1) and the vascular cell adhesion molecule (VCAM-1). Conjugated estrogen alone reduced levels of E-selectin by 17+/-14% (p<.00), ICAM-1 by 3+/-23% and VCAM-1 by 14+/-22%(p<.01) from respective pretreatment values. Conjugated estrogen combined with simvastatin also reduced levels of these cell adhesion molecules; E-selectin by 18+/-16%, ICAM-1 by 8+/-15% and VCAM-1 by 12+/-19% from respective pretreatment values (all p<.01). However, simvastatin alone did not change levels of E-selectin (+6+/-32%), ICAM-1 (+5+/-27%), or VCAM-1 (-3+/-26%) from respective pretreatment values. Significant and equivalent improvement in flow-mediated dilation was seen with each therapy: conjugated estrogen 4.0+/-2.6 to 10.2+/-3.9%, simvastatin 4.3+/-2.4 to 10.0+/-3.9%, conjugated estrogen plus simvastatin 4.6+/-2.0 to 9.8+/-2.6% (all p<.001 versus respective pretreatment baseline values). However, only therapies including conjugated estrogen reduced levels of cell adhesion molecules. Thus, therapies that improve nitric oxide bioactivity may not have comparable effects on anti-inflammatory potential.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL005003-02
Application #
6109275
Study Section
Cell Biology Integrated Review Group (CB)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code