Abstract 14580: Vascular Hypoxia Augments Thrombogenic Potential of Atherosclerotic Plaque; Interactive Contribution of HIF-1α and NF-κB
Introduction: The presence of vascular hypoxia had been demonstrated in atherosclerotic lesion. However, little is known about the relationship between vascular hypoxia and arterial thrombogenesis. Hypothesis: We assessed the hypothesis that vascular hypoxia promotes arterial thrombus formation.
Methods: A model of atherosclerosis was created by denudation of endothelium using balloon catheter on femoral artery in rabbit under feeding with a diet containing 0.5% cholesterol. Arterial thrombus formation was induced by balloon injury on atherosclerotic and normal arteries. Vascular hypoxia was immunohistochemically detected as pimonidazole (a marker of hypoxia) staining. Rabbit atherosclerotic plaques were also cultured to analyze the expression of prothrombotic factors under hypoxia (5% O2). Human coronary plaque hypoxia was assessed as the nuclear localization of hypoxia inducible factor (HIF)-1α in atherectomy tissues obtained from patients with stable (SAP, n = 16) or unstable angina pectoris (UAP, n = 16).
Results: Hypoxic area was localized in deep portion of atherosclerotic plaque and positively correlated with plaque size (r = 0.70, p < 0.01), macrophage area (r = 0.63, p < 0.01), the numbers of immunopositive nuclei for HIF-1α (r = 0.62, p < 0.01), nuclear factor-kappa B (NF-κB) (r = 0.42, p < 0.05) and tissue factor (TF) expression (r = 0.59, p < 0.01). Immunopositive areas for glycoprotein IIb/IIIa (platelets) and fibrin in thrombus were significantly larger in atherosclerotic, than in normal arteries (both p < 0.01), and significantly correlated with hypoxic area in arteries (platelets, r = 0.32, p < 0.05; fibrin, r = 0.87, p < 0.0001). Tissue levels of TF and plasminogen activator inhibitor-1 were increased in atherosclerotic plaque cultured under hypoxia, and were suppressed by inhibiting either HIF-1α or NF-κB (all p < 0.05; n = 5 each). The number of HIF-1α immunopositive nuclei was significantly more in plaques from patients with UAP than with SAP (p < 0.01) and in those containing thrombus (p < 0.05). The value was positively correlated with those of NF-κB immunopositive nuclei (r = 0.48, p < 0.01).
Conclusion: Vascular hypoxia augments thrombogenic potential of atherosclerotic plaque through the upregulation of prothrombotic factors.
- © 2012 by American Heart Association, Inc.