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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1909.)
© 2001 American Heart Association, Inc.

Vascular Biology

Increased Rate of Apoptosis in Intimal Arterial Smooth Muscle Cells Through Endogenous Activation of TNF Receptors

Audrey Niemann-Jönsson; Mikko P.S. Ares; Zhong-Qun Yan; D.-X. Bu; Gunilla Nordin Fredrikson; Lena Brånén; Isabella Pörn-Ares; Anna Hultgårdh Nilsson; Jan Nilsson

From the Department of Medicine (A.N.-J., M.P.S.A., G.N.F., L.B., J.N.) and the Division of Experimental Pathology (I.P.-A.), Department of Laboratory Medicine, Malmö University Hospital, Malmö; the Department of Cell and Molecular Biology (A.H.N.), Lund University, Lund; and the Center for Molecular Medicine (S.-Q.Y., D.-X.B.), Karolinska Institutet, Stockholm, Sweden.

Correspondence to Jan Nilsson, Department of Medicine, Malmö University Hospital, 205 02 Malmö, Sweden. E-mail jan.nilsson{at}medforsk.mas.lu.se

Intimal proliferation of smooth muscle cells (SMCs) is a key event in the vascular response to injury, including the early stages of atherosclerosis and restenosis after angioplasty. Tumor necrosis factor- (TNF-) has been reported to stimulate growth of cultured human SMCs, but activation of TNF receptors is also known to induce cell death by apoptosis. We report here that SMCs isolated from the neointima of injured rat aortas are characterized by increased expression of TNF- in response to interleukin-1ß and -interferon compared with medial SMCs. Basal and serum-stimulated DNA synthesis was higher in intimal than in medial SMCs. In contrast to previous findings on human SMCs, exposure to interleukin-1ß/-interferon or TNF- did not affect the growth of rat medial SMCs, inhibited DNA synthesis, and decreased cell numbers in cultures of intimal SMCs. Incubation of intimal SMCs with these cytokines also resulted in induction of terminal dUTP nick end-labeling positivity and caspase-3 expression, suggesting cell death by apoptosis, whereas medial cells were markedly less sensitive in this respect. Cytokine-induced apoptosis in intimal cells was effectively inhibited by treatment with antibodies against TNF receptors. These findings suggest that endogenous activation of TNF receptors may represent a way to limit accumulation of SMCs in injured arteries. This mechanism may also be important in SMC death in advanced atherosclerotic plaques.

Key Words: smooth musclecells • apoptosis • injury • cell replication

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