Abstract
Vascular smooth muscle cells (VSMC) growth plays a key role in the pathophysiology of vascular diseases. However, the molecular mechanisms controlling gene transcription in VSMC remain poorly understood. We previously identified, by differential display, a new gene (6A3-5) overexpressed in proliferating rat VSMC. In this study, we have cloned the full-length cDNA by screening a rat foetal brain cDNA library and investigated its functions. The 6A3-5 protein shows 4 putative conserved functional motifs: a DNA binding domain called ARID (AT-rich interaction domain), two recently described motifs (Osa Homology Domain), and a nuclear localization signal. The deduced protein sequence was observed to be 85% identical to the recently described human Osa2 gene. Immunolabelling, using an anti-6A3-5/Osa2 monoclonal antibody, showed a nuclear localization of the 6A3-5/Osa2 protein. In addition, PDGF upregulated 6A3-5/Osa2 expression at both the transcript and protein levels in a dose and time-dependent fashion. The pattern of upregulation by PDGF was reminiscent of the early responsive gene c-fos. The PDGF-induced upregulation of 6A3-5/Osa2 and proliferation of VSMC were significantly inhibited in a dose and sequence-dependent fashion by an antisense, but not by sense, scrambled or mismatched oligonucleotides directed against 6A3-5/Osa2. In VSMC of aortas derived from hypertensive (LH) rats, 6A3-5/Osa2 is overexpressed as compared to that in normotensive (LL) rats. The 6A3-5/Osa2-gene expression is downregulated by an ACE inhibitor and upregulated by exogenous AngiotensinII in LH rats. In summary, these results indicate that 6A3-5/Osa2 is an early activated gene that belongs to a new family of proteins involved in the control of VSMC growth.
Highlights
Vascular smooth muscle cell (VSMC) growth plays a critical role in different pathological conditions such as atherosclerosis [1] and its clinical complications
Vascular smooth muscle cells (VSMC) growth plays a key role in the pathophysiology of vascular diseases
The cloned gene has a 6569 bp cDNA sequence (GenBank accession number: AJ440711) and a deduced amino acid sequence corresponding to a 5276 bp open-reading frame (Figure 1(a))
Summary
Vascular smooth muscle cell (VSMC) growth plays a critical role in different pathological conditions such as atherosclerosis [1] and its clinical complications. Development of these vascular diseases is associated with a loss of vascular contractility counterbalanced by an increase of VSMC migration, proliferation, matrix secretion, and, in some cases, hypertrophy [2]. Many transcription factors (such as c-fos [6], Ets-1 [7], NFκB [8]) and the subsequent expression of a large number of genes (eg, alphaactin, Collagen IV, MCP-1, Endothelin-1, PDGF-A, TSP-1, bFGF, and PDGF A-chain [9]) are stimulated by AngII. The molecular mechanisms controlling gene transcription during these processes remain at this stage poorly understood
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