Activin and TR3 orphan receptor: two 'atheroprotective' genes as evidenced in dedicated mouse models.
1. Atherosclerosis is a multifactorial, inflammatory disease of the arterial vessel wall that is promoted by various well-defined risk factors. Although numerous genes, expressed in different vascular and inflammatory cells, have been implicated in this disease, it is widely appreciated that most of the genes and gene products vital for initiation and progression of atherosclerosis are unknown. 2. We follow two strategies in an attempt to make up for the void of essential knowledge. First, we study candidate genes that have not been implied in human atherosclerosis before, notably the differentiation factor activin A. 3. Second, we performed a genome-wide search by differential display reverse transcription-polymerase chain reaction. This study indicated potential involvement of the TR3 orphan receptor transcription factor in smooth muscle cell (SMC) (patho)physiology. 4. To reveal functional involvement of these proteins in SMC during atherosclerosis, we performed experiments with mouse models, adjusted either to the characteristics of a secreted protein or to that of an intracellular transcription factor. 5. The secreted protein activin A was studied in mice infected systemically with recombinant adenoviral vehicles, resulting in predominant hepatic expression and subsequent high protein levels in the circulation. 6. To study the role of TR3 in atherosclerosis, we generated transgenic mice in which promoter sequences were applied that direct expression of the transgenes to SMC of the arterial tree. 7. Two approaches were taken to induce the formation of SMC-rich lesions: (i) activation of femoral artery SMC by placement of a loosely fitting cuff; and (ii) ligation of the carotid artery. 8. The aim of the present review is to illustrate the different approaches that can be taken to assess the potential relevance of genes in atherosclerosis in carefully selected mouse models. 9. Based on the results described, we propose that both activin A and TR3 prevent excessive SMC proliferation.
Engelse
Marten A
MA
Department of Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Arkenbout
E Karin
EK
Pannekoek
Hans
H
de Vries
Carlie J M
CJ
D028341:Activins / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics* / Q000517:prevention & control*; D004195:Disease Models, Animal; D006801:Humans; D028322:Inhibin-beta Subunits / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000235:genetics*
C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits