Role for Cell Division Autoantigen 1 in Mediating TGF-β Downstream Signaling and Extracellular Matrix Protein Production in Diabetic Atherosclerosis

REVIEW ARTICLE

Zemin Cao^1, Mark E Cooper^1, Terri J Allen^1, Ban-Hock Toh² and Zhonglin Chai¹

Affiliations: ¹Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia and ²Autoimmunity Laboratory, Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia

ABSTRACT

Atherosclerosis is associated with the development of various cardiovascular diseases, including myocardial infarction and stroke, which represent some of the leading causes of death in the western world. The presence of diabetes is an important risk factor for the development and progression of atherosclerosis. Excess accumulation of extracellular matrix (ECM) proteins in the vasculature is considered to play an important role in these vascular diseases. Cell division autoantigen 1 (CDA1) was identified as a key player in modulating downstream signaling of transforming growth factor-beta (TGF-b) leading to regulation of the production of ECM proteins, sharing anti-proliferative and profibrotic properties with TGF-b. The gene and protein expression levels of CDA1 were elevated in the aortas of diabetic apolipoprotein E knockout mice, accompanied by increased levels of TGF-b, connective tissue growth factor (CTGF), and various ECM proteins. In cultured mouse vascular smooth muscle cells, TGF-b treatment was associated with increased CDA1 expression. Knockdown of CDA1 by siRNA, delivered by retroviral and adenoviral constructs, was associated with reduced TGF-b signaling, shown by attenuated Smad3 phosphorylation and its transcriptional activities on TGF-b stimulation. By contrast, overexpression of CDA1 increased the gene expression of TGF-b, TGF-b receptor type 1, CTGF, and other ECM proteins. It appears that CDA1 plays an important role in mediating TGF-b signaling and ECM proteins production in the vasculature and in particular in diabetes-associated atherosclerosis.

Keywords: Atherosclerosis, diabetes Mellitus, TGF-b, cell division autoantigen 1, extracellular matrix proteins, CTGF

Correspondence: Zemin Cao, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Victoria 8004, Australia. Tel:
61 385321231; Fax:
61 385321100; e-mail: zemin.cao@bakeridi.edu.au