Advisory Committee Chair
Anupam Agarwal
Advisory Committee Members
Daniel F Balkovetz
Peter J Detloff
Thomas M Ryan
Victor M Darley-Usmar
Document Type
Dissertation
Date of Award
2007
Abstract
Ischemic tissue and organ dysfunction occur in a variety of cardiovascular diseases. The hypoxic environment created during ischemic injury activates cytoprotective genes, of which heme oxygenase-1 (HO-1) is of great interest. This microsomal inducible enzyme is involved in the homeostasis of prooxidant heme, which is released from heme proteins upon injury. HO-1 responds to a variety of oxidative stress associated stimuli. HO-1 expression has been implicated as a protective response in diverse disease states which has been attributed to the beneficial properties of the by products iron, carbon monoxide and biliverdin/bilirubin. Regulation of expression of HO-1 is also significant, as ischemic insults induce a repair response in the injured tissue. The angiogenic response to injury, discussed in this thesis, involves the stromal cell-derived factor-1 (SDF-1), which plays a major role in migration, recruitment and retention of endothelial progenitor cells (EPC) to sites of ischemic injury and contributes repair. Direct evidence is presented demonstrating an important role for the induction of HO-1 in mediating the proangiogenic effects of SDF-1. Nanomolar concentrations of SDF-1 induced HO-1 in endothelial cells through a PKC-ζ dependent and VEGF- independent mechanism. SDF-1 also mediates transcriptional regulation by activation of the HO-1 promoter. A minimal enhancer region is identified within the human HO-1 gene which participated in the transcriptional regulation. SDF-1 promotes angiogenic response by an HO-1 dependent mechanism. The SDF-1 induced endothelial tube formation, migration and capillary sprouting are all dependent on HO-1. Carbon monoxide (CO), a by product of HO-1 reaction can substitute for HO-1 and induce capillary sprouting. SDF-1 and HO-1 derived CO also promote phosphorylation of vasodilator-stimulated phosphoprotein (VASP). CO promotes redistribution of VASP to filopodia of migrating EPC in the absence of HO-1. The functional significance of HO-1 in angiogenesis is confirmed in Matrigel plug, wound healing and retinal ischemia models in vivo. Impaired wound healing as well as defective homing and re-endothelialization in retinal vasculature of EPC following retinal ischemia are associated with HO-1 deficiency. These findings demonstrate a novel mechanistic role for HO-1 in SDF-1 mediated angiogenesis and provide new avenues for therapeutic approaches in vascular repair.
Recommended Citation
Deshane, Jessy, "Regulation of HO-1 and its role in angiogenesis" (2007). All ETDs from UAB. 6808.
https://digitalcommons.library.uab.edu/etd-collection/6808