Genomic instability in the type II TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells.

Abstract

Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-␤ 1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-␤ 1 (T ␤ R-II), causing acquired resistance to TGF-␤ 1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A 10 microsatellite within T ␤ R-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in T ␤ R-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A 10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-␤ 1. We propose that microsatellite instability in T ␤ R-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions. ( J. Clin. Invest. 1997.

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

“…5 This hypothesis remains attractive, because somatic mutations in the TGF-␤ signaling pathway are relatively common and may contribute to the pathogenesis of certain tumors 12 and atherosclerosis. 13 In the present study, we demonstrate that BMPR-II mRNA and protein expression is mainly localized to the endothelium in the normal pulmonary circulation, although it is also expressed by myofibroblasts comprising concentric intimal lesions in severe PH. In addition, we report that pulmonary vascular BMPR-II expression is reduced in PPH cases, most markedly in those PPH cases with an underlying mutation in the BMPR2 gene.…”

Molecular Studies on Coronary Artery Disease—A Review

“…It is noteworthy that microsatellite sequences were mutated in the atherosclerotic tissues but not in normal vascular tissues from the same patients. The observations indicate that there is a common pattern of microsatellite sequence mutation in atherosclerotic plaque collected from different patients and from experimental animals [113,114].…”

“…In a small fraction of cancers, mainly sporadic human tumors, defective repair of mismatched bases results in an increased mutation rate and consequent widespread microsatellite instability [112]. Mc Caffrey et al [113] found an increased mutation rate of microsatellite sequences in patients with cardiovascular atherosclerotic lesions. The demonstration of microsatellite instability in human atherosclerotic plaques suggests that genomic destabilization, which may also affect other genes, can result in the misregulation of the cells harboring these mutations and may play a pivotal role in atherosclerotic mechanisms.…”

Structural Variablity of Leucocyte Genome and Arterial Cells in Human Atherosclerosis

“…Одной из первых соматических мутаций, обнару-женных в ГМК атеросклеротических бляшек коро-нарных и сонных артерий человека, является мутация в полиадениновом тракте гена рецептора трансфор-мирующего ростового фактора β, II типа (TGFBR2) [21]. В связи с тем, что данная мутация выявлена в единичных первичных и рестенотических атеро-склеротических бляшках артерий, полагают, что она не принимает участие в патогенезе заболевания [22,23].…”