Tumor necrosis factor-alpha promotes atherosclerotic lesion progression in APOE*3-Leiden transgenic mice.
OBJECTIVE
Tumor necrosis factor-alpha (TNFalpha) is a pleiotropic cytokine exerting both inflammatory and cell death modulatory activity, and is thought to play a role in the pathogenesis of atherosclerosis. Studies in mice indicated that TNFalpha affects atherosclerosis minimally or not under conditions that allow fatty streak formation. Here, we examined the possible role of TNFalpha in advanced and complex atherosclerotic lesions.


RESULTS
To induce atherosclerosis, TNFalpha-deficient (Tnf-/-) APOE*3-Leiden and control APOE*3-Leiden only mice were fed a cholesterol-rich diet. Comparable levels of plasma cholesterol and triglycerides and the systemic inflammatory parameters, serum amyloid A and soluble intercellular adhesion molecule-1 were found in APOE*3-LeidenTnf-/- and control mice. Although absence of TNFalpha did not affect the quantitative area of atherosclerosis, APOE*3-LeidenTnf-/- mice had a higher relative number of early lesions (46.1% vs. 21.4%) and a lower relative number of advanced lesions (53.9% vs. 78.6%, P=0.04). In addition, the advanced lesions in APOE*3-LeidenTnf-/- mice showed less necrosis (9.9+/-12.1% vs. 23.4+/-19.3% of total lesion area, P=0.04) and an increase in apoptosis (1.5+/-1.5% vs. 0.4+/-0.6% of total nuclei, P=0.03).


CONCLUSIONS
Our data indicate that TNFalpha stimulates the formation of lesions towards an advanced phenotype, with more lesion necrosis and a lower incidence of apoptosis.
Boesten
Lianne S M
LS
Department of General Internal Medicine, Leiden University Medical Center, The Netherlands. lsm.boesten@pg.tno.nl
Zadelaar
A Susanne M
AS
van Nieuwkoop
Anita
A
Gijbels
Marion J J
MJ
de Winther
Menno P J
MP
Havekes
Louis M
LM
van Vlijmen
Bart J M
BJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D001161:Arteriosclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D000685:Serum Amyloid A Protein / Q000032:analysis; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D000685:Serum Amyloid A Protein; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol