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The role of vitronectin receptor (vß3) and tissue factor in the pathogenesis of transplant coronary vasculopathy

Mohamad H. Yamani, MD^*||,*, Carolina S. Masri, MD^*||, Norman B. Ratliff, MD, Meredith Bond, PhD, Randall C. Starling, MD, MPH, FACC^*||, E. Murat Tuzcu, MD^*, Patrick M. McCarthy, MD^|| and James B. Young, MD, FACC^*||

^* Department of Cardiology, Learner Research Institute, Cleveland, Ohio, USA
Department of Anatomic Pathology, Learner Research Institute, Cleveland, Ohio, USA
Department of Molecular Cardiology, Learner Research Institute, Cleveland, Ohio, USA
Department of Cardiothoracic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^|| Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio, USA

View larger version (93K): [in a new window]   Figure 1 vß3 and tissue factor immunohistochemistry staining in relation to coronary vasculopathy. Positive staining (brown) of both vß3 (E, arrow, vascular endothelium) and tissue factor (F, myocardial interstitium) in a patient with coronary vasculopathy demonstrated on intravascular ultrasound (D) compared with a patient without evidence of coronary vasculopathy (A, B, C). Bar = 50 µm.

View larger version (25K): [in a new window]   Figure 2 Western blot analysis showing evidence of increased expression of vß3 (A, 2.7-fold) and tissue factor (TF) (B, 7.9-fold) in the presence of coronary vasculopathy (CV) (coronary maximal intimal thickness [CMIT] >0.3 mm) compared with patients without CV (CMIT 0.3 mm). GAPDH = glyceraldehyde-3-phosphate dehydrogenase.

View larger version (14K): [in a new window]   Figure 3 Myocardial vß3 and tissue factor (TF) protein expression in relation to the severity of coronary vasculopathy (CV). Relative decrease of vß3 expression is noted in the presence of advanced CV (>0.5 mm). GAPDH = glyceraldehyde-3-phosphate dehydrogenase.

View larger version (11K): [in a new window]   Figure 4 Correlation of myocardial vß3 protein expression with cellular rejection score during the first six months of transplant in the absence of post-transplant ischemic injury/fibrosis. GAPDH = glyceraldehyde-3-phosphate dehydrogenase.

View larger version (10K): [in a new window]   Figure 5 Correlation of myocardial vß3 protein expression with severity of coronary vasculopathy in patients with post-transplant ischemia/fibrosis. CMIT = coronary maximal intimal thickness; GAPDH = glyceraldehyde-3-phosphate dehydrogenase.

View larger version (15K): [in a new window]   Figure 6 Myocardial vß3 and tissue factor (TF) protein expression in patients with coronary vasculopathy in relation to the presence or absence of post-transplant ischemic injury/fibrosis. A significant decrease of vß3 expression is noted in patients with post-transplant ischemic injury/fibrosis. GAPDH = glyceraldehyde-3-phosphate dehydrogenase.

View larger version (26K): [in a new window]   Figure 7 Biopsy score in patients with coronary vasculopathy in relation to the presence or absence of post-transplant ischemic injury/fibrosis. Patients with fibrosis have reduced cellular rejection score at one year (Y), mainly during 6 to 12 months of transplant (Y2). *p = 0.05; Y, fibrosis versus no fibrosis. **p = 0.006; Y2, fibrosis versus no fibrosis. Y1 = cellular rejection score during the first 6 months of transplant.

View larger version (44K): [in a new window]   Figure 8 A schematic representation showing the relationship between vß3 and tissue factor (TF). vß3 is expressed on many cells including platelets, lymphocytes, smooth muscle cells, vascular endothelial cells, and macrophages. vß3 has been shown to co-stimulate the release of tumor necrosis factor-alpha (TNF-) in macrophages. Tumor necrosis factor-alpha in turn induces tissue factor expression. Tissue factor expression is also induced by interleukin-1 (IL-1) and oxidized low density lipoprotein (LDL). Tissue factor binds factor VIIa to form a complex that converts factor X to its active form, Xa, which in turn accelerates the conversion of prothrombin to thrombin. Prothrombin serves as a ligand to vß3 and its binding to vß3 also accelerates the conversion of prothrombin to thrombin.