Possible participation of Fas-mediated apoptosis in the mechanism of atherosclerosis.
Apoptosis is a programmed cell death that plays a major role during development, homeostasis, and in many diseases. Recent evidence has demonstrated the death of vascular smooth muscle cells (VSMCs) within advanced human atheroma. In the rat balloon-injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). To clarify the mechanisms that trigger apoptosis in atherosclerotic lesions, we examined whether cytokines released from macrophages can modulate Fas, a death signal, in cultured human VSMCs. Simultaneous treatment with interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) but not with each cytokine alone induced upregulation of Fas in VSMCs. However, coincubation with NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Fas induced by IL-1 and TNF-alpha. Incubation with sodium nitroprusside, a NO donor, also induced upregulation of Fas in VSMCs. Furthermore, fluorescent nuclear staining with Hoechst 33258 revealed that monoclonal antibody to human Fas significantly enhanced NO-induced apoptotis in VSMCs. These findings suggest that macrophage-derived cytokines can induce upregulation of Fas through a NO-dependent mechanism in VSMCs. Thus, Fas-mediated apoptosis may regulate apoptotic death of VSMCs during atherogenesis.
Fukuo
K
K
Department of Geriatric Medicine, Osaka University Medical School, Japan.
Nakahashi
T
T
Nomura
S
S
Hata
S
S
Suhara
T
T
Shimizu
M
M
Tamatani
M
M
Morimoto
S
S
Kitamura
Y
Y
Ogihara
T
T
D000818:Animals; D000918:Antibody Specificity; D001011:Aorta / Q000166:cytology / Q000293:injuries; D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002339:Carotid Arteries / Q000166:cytology; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects; D016207:Cytokines / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008264:Macrophages / Q000737:chemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000502:physiology; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D016207:Cytokines; D019014:fas Receptor; D009569:Nitric Oxide