The Expression of TGF-β Receptors in Human Atherosclerosis: Evidence for Acquired Resistance to Apoptosis due to Receptor Imbalance

• Published in: Journal of molecular and cellular cardiology Vol. 31; no. 9; pp. 1627 - 1642
• Main Authors: McCaffrey, Timothy A, Du, Baoheng, Fu, Chenzhong, Bray, Paula J, Sanborn, Timothy A, Deutsch, Ezra, Tarazona, Norman, Shaknovitch, Alexander, Newman, Gregg, Patterson, Cam, Bush Jr, Harry L
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.1999
• Subjects: Activin Receptors, Type I; Apoptosis; Arteriosclerosis - genetics; Arteriosclerosis - pathology; Arteriosclerosis - physiopathology; Atherectomy; Atherosclerosis; Carotid Stenosis - genetics; Carotid Stenosis - pathology; Carotid Stenosis - physiopathology; Cell Division - drug effects; Cloning, Molecular; Coronary Disease - genetics; Coronary Disease - pathology; Coronary Disease - physiopathology; Endarterectomy, Carotid; Gene therapy; Humans; Immunohistochemistry; Interferon-γ; Models, Cardiovascular; Protein-Serine-Threonine Kinases - genetics; Receptors; Receptors, Transforming Growth Factor beta - genetics; Recombinant Proteins - biosynthesis; Recurrence; Resistance; Restenosis; Retrovirus; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Transcription, Genetic; Transfection; Transforming Growth Factor beta - pharmacology; Transforming growth factor- β; Resistance; Restenosis; Retrovirus; Receptors; Interferon-γ; Atherosclerosis; Transforming growth factor- β; Gene therapy; Apoptosis
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.1999.0999

The degree of cellularity in vascular lesions is determined by the balance between the migration and proliferation of cells relative to their rate of egress and apoptosis. Transforming growth factor- β1can act as a potent antiproliferative and apoptotic factor for proliferating vascular cells. Our laboratory has previously identified cells cultured from human vascular lesions that are resistant to the antiproliferative effect of TGF- β1due to an acquired mutation in the Type II receptor for TGF- β1. In the present studies, the expression of the Type I and II receptors in coronary and carotid atherosclerotic lesions was analysed by immunostaining, RT-PCR, and in situ RT-PCR. Levels of the Type I and Type II receptors varied widely within lesions, with the highest levels in the fibrous cap and at discrete foci within the lesion. Regions of smooth muscle-like cells (SMC) were commonly found that were Type I positive but Type II receptor negative. In 43 cell lines cultured from 126 human lesions, 84% of the lesion-derived cell (LDC) cultures exhibited functional resistance to the antiproliferative effect of TGF- β1. This resistance was conferred against TGF- β1, TGF- β2, and TGF- β3, but not interferon- γ or mimosine. While normal SMC exhibited a four-fold increase in the rate of apoptosis after TGF-β1 treatment, most LDC were resistant to apoptosis in response to TGF- β1. Resistant cells exhibited selective loss of Type II receptor expression, and retroviral transfection of Type II receptor cDNA partially corrected the functional deficit. Thus, resistance to apoptosis may lead to the slow proliferation of resistant cell subsets, thereby contributing to the progression of atherosclerotic and restenotic lesions.