Potential roles of osteopontin and α _V β ₃ integrin in the development of coronary artery restenosis after angioplasty

Abstract

Angioplasty procedures are increasingly used to reestablish blood flow in blocked atherosclerotic coronary arteries. A serious complication of these procedures is reocclusion (restenosis), which occurs in 30-50% of patients. Migration of coronary artery smooth muscle cells (CASMCs) to the site of injury caused by angioplasty and subsequent proliferation are suggested mechanisms of reocclusion. Using both cultured human CASMCs and coronary atherectomy tissues, we studied the roles of osteopontin (OPN) and one of its receptors, ␣ v ␤ 3 integrin, in the pathogenesis of coronary restenosis. We also measured the plasma levels of OPN before and after angioplasty and determined the effect of exogenous OPN on CASMC migration, extracellular matrix invasion, and proliferation. We found that cultured CASMCs during log phase of growth and smooth muscle cell layer of the coronary atherosclerotic tissues of patients express both OPN mRNA and protein at a significantly elevated level compared with controls. Interestingly, whereas the baseline plasma OPN levels in control samples were virtually undetectable, those in patient plasma were remarkably high. We also found that interaction of OPN with ␣ v ␤ 3 integrin, expressed on CASMCs, causes migration, extracellular matrix invasion, and proliferation. These effects were abolished when OPN or ␣ v ␤ 3 integrin gene expression in CASMCs was inhibited by specific antisense S-oligonucleotide treatment or OPN-␣ v ␤ 3 interaction was blocked by treatment of CASMCs with antibodies against OPN or ␣ v ␤ 3 integrin. Our results demonstrate that OPN and ␣ v ␤ 3 integrin play critical roles in regulating cellular functions deemed essential for restenosis. In addition, these results raise the possibility that transient inhibition of OPN gene expression or blocking of OPN-␣ v ␤ 3 interaction may provide a therapeutic approach to preventing restenosis.

Osteopontin Induces AP-1-mediated Secretion of Urokinase-type Plasminogen Activator through c-Src-dependent Epidermal Growth Factor Receptor Transactivation in Breast Cancer Cells

“…The level of OPN was high in the plasma of patients with breast cancer and has been shown to correlate with poor prognosis of breast cancer (10,12). OPN regulates cell adhesion, cell migration, ECM invasion, and cell proliferation by interacting with its receptor ␣ v ␤ 3 integrin in various cell types (6). Previous data indicated that OPN induces pro-matrix metalloproteinase-2 (pro-MMP-2) activation and urokinase-type plasminogen activator (uPA) secretion, cell motility, ECM invasion, and tumor growth (13)(14)(15).…”

“…This protein has a functional thrombin cleavage site and is a substrate for tissue transglutaminase (2). It binds with several integrins and CD44 variants in an RGD sequencedependent and -independent manner (5,6). This protein is involved in normal tissue-remodeling process such as bone resorption, angiogenesis, wound healing, and tissue injury as well as certain diseases such as restenosis, atherosclerosis, tumorigenesis, and autoimmune diseases (6 -8).…”

The Integrin α9β1 Binds to a Novel Recognition Sequence (SVVYGLR) in the Thrombin-cleaved Amino-terminal Fragment of Osteopontin

“…Osteopontin is present at high concentrations in diseases associated with tissue remodeling, including granuloma formation (12) and coronary restenosis (13,14), suggesting that this molecule might contribute to the process of remodeling. Osteopontin contains a predicted thrombin cleavage site (15) and appears to be cleaved at this site in vivo (16,17).…”

Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB

“…The confirmed extent of induction of OPN mRNA levels in response to hypertensive disease was particularly intriguing due to the previous implications that OPN regulates VSMC proliferation and migration and is overexpressed during postangioplasty restenosis (15,35,50). In addition, OPN is a matricellular gene that is known to be transcriptionally regulated by ANG II and ERK signaling (7).…”

“…OPN is a marker of proliferation in rat VSMCs, and its expression in cultured VSMCs correlates with the downregulation of contractile proteins, suggesting a switch from the contractile to the proliferative phenotype (15,17,50,56). OPN plays a role in coronary artery postangioplasty restenosis through its chemotactic properties, where it mediates smooth muscle cell extracellular matrix invasion of the intimal layer (35). Moreover, OPN has been referred to as a "delayed early gene" because of its role in cell proliferation following mitogenic stimulation in arterial smooth muscle cells (15).…”