transforming-growth-factor-beta and Death--Sudden

Transforming growth factor-beta (TGF-beta) 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-beta modulates gene transcription. Our objective was to define the actions of TGF-beta during lesion progression in humans by examining the expression of Smads in relation to TGF-beta-mediated responses.. 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 p21(Waf1) 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.. In human atherosclerotic lesions, the actions of TGF-beta appear restricted to SMCs in fibrous plaques and macrophages in fatty streaks/fibrofatty lesions. The lack of key TGF-beta signaling components in SMCs of fibrofatty lesions indicates impaired ability of these cells to initiate TGF-beta-mediated Smad-dependent transcriptional responses.

Topics: Adult; Aged; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Cell Cycle Proteins; Cell Differentiation; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p21; Death, Sudden; DNA-Binding Proteins; Female; Fibrosis; Humans; Lipids; Macrophages; Male; Middle Aged; Monocytes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; RNA Splicing; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Proteins