Angiogenesis is the physiological adaptive response of a tissue to hypoxia. The coronary collateral circulation of the heart represents such an adaptive response and is an important determinant in the extent of tissue damage following myocardial infarction. Autopsy studies have shown that only 50 percent of patients with coronary artery stenosis develop collaterals. A fundamental challenge in understanding the angiogenic response to ischemia in the clinical setting is to elucidate the basis for interindividual differences in the degree of collateral blood vessel formation. Recent evidence demonstrates the importance of differences between patients in the hypoxic regulation of the angiogenic growth factor, vascular endothelial growth factor (VEGF) in determining the extent of collateral blood vessel formation. Specifically, individuals who upregulate VEGF to a greater degree with hypoxia have more collateral blood vessels. The investigators intend to investigate the mechanism for this heterogeneity in the hypoxic regulation of VEGF. Accordingly, the specific aims of this project are: (1) Analysis of interindividual heterogeneity in hypoxia-inducible VEGF production in patients with obstructive sleep apnea syndrome (OSAS) in vivo and in vitro and its relationship to coronary collaterals; (2) Determination of the molecular mechanism for interindividual heterogeneity in VEGF production in response to hypoxia. These studies may lead to the development of new strategies to increase VEGF production in the setting of ischemic heart disease and thereby promote therapeutic angiogenesis. In addition, understanding the mechanism of interindividual heterogeneity in VEGF production in response to hypoxia would be of tremendous importance for understanding and predicting the natural history of a wide variety of diseases involving VEGF including tumor angiogenesis, diabetic retinopathy, rheumatoid arthritis, and inflammatory bowel disease.
| Levy, Andrew P; Larson, Martin G; Corey, Diane et al. (2004) Haptoglobin phenotype and prevalent coronary heart disease in the Framingham offspring cohort. Atherosclerosis 172:361-5 |
| Lavie, Lena; Lotan, Rachel; Hochberg, Irit et al. (2003) Haptoglobin polymorphism is a risk factor for cardiovascular disease in patients with obstructive sleep apnea syndrome. Sleep 26:592-5 |
| Roguin, Ariel; Koch, Werner; Kastrati, Adnan et al. (2003) Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes. Diabetes Care 26:2628-31 |
| Levy, Andrew P; Hochberg, Irit; Jablonski, Kathleen et al. (2002) Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol 40:1984-90 |
| Melamed-Frank, M; Lache, O; Enav, B I et al. (2001) Structure-function analysis of the antioxidant properties of haptoglobin. Blood 98:3693-8 |
