Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-[beta] in a murine diabetic model of atherosclerosis

• Published in: Diabetologia 2010-01, Vol.53 (1), p.170
• Main Authors: Pham, Y, Tu, Y, Wu, T, Allen, T J, Calkin, A C, Watson, A M, Li, J, Jandeleit-dahm, K A, Toh, B-h, Cao, Z, Cooper, M E, Chai, Z
• Format: Article
• Language: English
• Subjects: Adenoviruses; Atherosclerosis; Cell division; Connective tissue; Coronary vessels; Cyclin-dependent kinases; Diabetes; Extracellular matrix; Genes; Growth factors; Insects; Kinases; Proteins; Smooth muscle
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-009-1555-9

Excess accumulation of vascular extracellular matrix (ECM) is an important pathological process in cardiovascular diseases including diabetes-associated atherosclerosis. We explored how a recently identified molecule, cell division autoantigen 1 (CDA1), influences the profibrotic TGF-β pathway leading to vascular ECM accumulation. Expression levels of genes encoding for CDA1, TGF-β and connective tissue growth factor (CTGF) were examined in aorta from Apoe -/- mice with or without diabetes. We used retroviral and adenoviral constructs to knockdown or overexpress Tspyl2, the gene encoding CDA1, in mouse vascular smooth muscle cells (VSMCs) with or without TGF-β treatment in order to demonstrate the role of CDA1 in TGF-β signalling. In vivo studies indicated that the mRNA levels of CDA1-encoding gene Tspyl2 and protein levels of CDA1 were elevated in the aorta of diabetic Apoe -/- mice, accompanied by increased levels of Tgf-β (also known as Tgfb1), Ctgf and ECM accumulation. In vitro studies in vascular cells showed that TGF-β treatment rapidly increased CDA1 protein levels, which then amplified TGF-β signalling leading to upregulation of ECM genes. Knockdown of CDA1-encoding gene Tspyl2 to reduce cellular CDA1 level markedly attenuated TGF-β-stimulated MAD homologue 3 (drosophila; SMAD3) phosphorylation and transcriptional activities. CDA1 overproduction increased and Tspyl2 knockdown decreased expression of TGF-β receptor type I, TβrI (also known as Tgfbr1), but not TGF-β receptor type II, TβrII (also known as Tgfbr2), providing a mechanism for CDA1's action in modulating TGF-β signalling. Knockdown of CDA1-encoding gene Tspyl2 also blocked the profibrotic effect of TGF-β in VSMCs. CDA1 plays an important role in vascular ECM accumulation by amplifying TGF-β signalling. This is critical for the profibrotic effect of TGF-β in the vasculature. CDA1 is therefore a potential target for attenuating vascular ECM accumulation caused by enhanced TGF-β action, as seen in diabetic atherosclerosis.