Abstract
Objective
Osteopontin (OPN) is a multifunctional protein found in abundance in atherosclerotic
plaques. Angiotensin II (Ang II) promotes atherosclerosis by inducing adhesion and
migration of vascular smooth muscle cells (VSMCs). MicroRNAs (miRNAs) are critical
regulators of protein expression. However, the relationship between Ang II, miRNAs
and OPN has yet to be fully explored.
Methods and results
Using cultured VSMCs, we found that Ang II increased cellular OPN protein expression
4 h after treatment by 420 ± 54% (p < 0.03) in a translation dependent manner. Sequence analysis revealed a putative
binding site for mir181a and raised the possibility that miR181a is a potential regulatory
mechanism for OPN expression. We demonstrated that Ang II decreased miR181a expression
by 52 ± 7% (p < 0 .0001) and overexpressing miR181a inhibited Ang II induced increases in OPN protein
expression by 69 ± 9% (p < 0.05). Furthermore, we demonstrated that miR181a is functionally important in that
overexpression of miR181a inhibited VSMCs adhesion to collagen in response to Ang
II as compared to controls by 36 ± 4%. (p < 0.05)
Conclusions
These results demonstrate that miR181a regulates OPN expression and that altering
miR181a expression may be a novel therapeutic approach to modulate OPN protein expression.
Highlights
- Ang II increases OPN expression in a translation dependent manner in VSMCs.
- Ang II decreases mir181a expression in VSMCs.
- Overexpression of mir181a inhibits Ang II induced OPN expression in VSMCs.
- OPN is essential for adhesion of VSMCs to collagen substrates.
- Overexpression of mir181a decreases adhesion of VSMCs to collagen substrates.
Keywords
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References
- Vasoprotective and atheroprotective effects of angiotensin (1–7) in apolipoprotein E-deficient mice.Arterioscler Thromb Vasc Biol. 2010; 30: 1606-1613
- Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.Am J Physiol Cell Physiol. 2007; 292: C82-C97
- Angiotensin II and atherosclerosis.Am J Cardiol. 2001; 87: 25C-32C
- Vascular smooth muscle cells derived from atherosclerotic human arteries exhibit greater adhesion, migration, and proliferation than venous cells.J Surg Res. 2002; 104: 22-28
- Inflammation and atherosclerosis.Annu Rev Pathol. 2006; 1: 297-329
- Inflammation in atherosclerosis.Nature. 2002; 420: 868-874
- Inflammation and atherosclerosis.Circulation. 2002; 105: 1135-1143
- Angiotensin II-induced osteopontin expression in vascular smooth muscle cells involves Gq/11, Ras, ERK, Src and Ets-1.Hypertens Res. 2008; 31: 987-998
- Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification.Curr Atheroscler Rep. 2009; 11: 206-213
- Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone.Endocrinology. 2001; 142: 1325-1332
- The multifaceted roles of osteopontin in cell signaling, tumor progression and angiogenesis.Curr Mol Med. 2006; 6: 819-830
- Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques.J Clin Invest. 1993; 92: 1686-1696
- Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta.J Clin Invest. 1993; 92: 2814-2820
- Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice.J Clin Invest. 2003; 112: 1318-1331
- Role of osteopontin in adhesion, migration, cell survival and bone remodeling.Exp Oncol. 2004; 26: 179-184
- Osteopontin: role in cell signaling and cancer progression.Trends Cell Biol. 2006; 16: 79-87
- Osteopontin stimulates vascular smooth muscle cell migration by inducing FAK phosphorylation and ILK dephosphorylation.Biochem Biophys Res Commun. 2007; 356: 13-19
- Osteopontin-stimulated vascular smooth muscle cell migration is mediated by beta 3 integrin.Exp Cell Res. 1994; 214: 459-464
- Osteopontin deficiency in rat vascular smooth muscle cells is associated with an inability to adhere to collagen and increased apoptosis.Lab Invest. 2000; 80: 1603-1615
- Micro RNAs in animal development.Cell. 2006; 124: 877-881
- microRNA functions.Annu Rev Cell Dev Biol. 2007; 23: 175-205
- Characterization of phosphatidylinositol-specific phospholipase C from cultured vascular smooth muscle cells.J Biol Chem. 1991; 266: 15498-15504
- A novel aortic smooth muscle cell line obtained from p53 knock out mice expresses several differentiation characteristics.Biochem Biophys Res Commun. 1997; 238: 154-158
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.Methods. 2001; 25: 402-408
- Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells.Circ Res. 1998; 82: 7-12
- Autocrine secretion of osteopontin by vascular smooth muscle cells regulates their adhesion to collagen gels.Am J Pathol. 1996; 149: 259-272
- Angiotensin II, atherosclerosis, and aortic aneurysms.J Clin Invest. 2000; 105: 1525-1526
- Reactive oxygen species and angiotensin II signaling in vascular cells – implications in cardiovascular disease.Braz J Med Biol Res. 2004; 37: 1263-1273
Bhattacharya SD, Garrison J, Guo H, et al. Micro-RNA-181a regulates osteopontin-dependent metastatic function in hepatocellular cancer cell lines, Surgery, 148, 291–7.
- MicroRNA regulation by RNA-binding proteins and its implications for cancer.Nat Rev Cancer. 2011; 11: 644-656
- MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation.J Immunol. 2010; 184: 6053-6059
- Angiotensin II and cell-matrix adhesion: PKCepsilon is essential.Cardiovasc Res. 2005; 67: 6-8
Zhu N, Zhang D, Chen S, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration, Atherosclerosis, 215, 286–93.
Article Info
Publication History
Published online: March 04, 2013
Accepted:
January 21,
2013
Received in revised form:
January 2,
2013
Received:
June 19,
2012
Identification
Copyright
© 2013 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
