Published online before print May 27, 2004, doi: 10.1161/01.ATV.0000133605.89421.79
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© 2004 American Heart Association, Inc.
Vascular Biology |
Smad Expression in Human Atherosclerotic Lesions
Evidence for Impaired TGF-ß/Smad Signaling in Smooth Muscle Cells of Fibrofatty Lesions
From the Baker Medical Research Institute (N.K., A.A., A.B.), Alfred Hospital, Melbourne, Victoria, Australia; and the Institute of Experimental Cardiology (N.K., Y.A., O.I., V.S., E.T.), Russian Cardiology Research Industrial Complex, Moscow, Russia.
Correspondence to Dr Alex Bobik, Cell Biology Laboratory, Baker Medical Research Institute, Alfred Hospital, St Kilda Road Central, PO Box 6492, Melbourne, Vic 8008, Australia. E-mail alex.bobik{at}baker.edu.au
Objective— Transforming growth factor-beta (TGF-ß) has been implicated in the pathogenesis of human atherosclerosis but its actions during lesion progression are poorly understood. Smad2, Smad3, and Smad4 proteins are signaling molecules by which TGF-ß modulates gene transcription. Our objective was to define the actions of TGF-ß during lesion progression in humans by examining the expression of Smads in relation to TGF-ß–mediated responses.
Methods and Results— Immunohistochemistry and reverse-transcription polymerase chain reaction demonstrated Smad2, Smad3, and Smad4 expression in macrophages of fibrofatty lesions and their upregulation after differentiation of monocytes to macrophages. The major Smad splice variants expressed by the macrophages were those that are transcriptionally most active. Macrophages also expressed cyclin inhibitors whose expression is induced via Smad proteins. The cytoplasmic location of p21Waf1 suggests it may protect macrophages from apoptosis. Smooth muscle cells (SMCs) within the fibrofatty lesions did not express the Smad proteins or the cyclin inhibitors. SMCs of fibrous plaques expressed all 3 Smad proteins.
Conclusions— In human atherosclerotic lesions, the actions of TGF-ß appear restricted to SMCs in fibrous plaques and macrophages in fatty streaks/fibrofatty lesions. The lack of key TGF-ß signaling components in SMCs of fibrofatty lesions indicates impaired ability of these cells to initiate TGF-ß–mediated Smad-dependent transcriptional responses.
The actions of TGF-ß in human atherosclerotic lesions were defined by examining the expression of Smad proteins in relation to TGF-ß–mediated responses. Expression of Smad proteins was restricted to macrophages of fibrofatty lesions and SMCs of fibrous plaques. Smad-dependent TGF-ß signaling appeared to be impaired SMCs of fibrofatty lesions.
Key Words: Smad • p15INK4B • p21Waf1 • collagen • human atherosclerotic lesions
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