: While recent years have witnessed an explosion of studies of therapeutic angiogenesis in cardiovascular disease, detailed understanding of regulation of angiogenic response remains an elusive goal. In particular, there is little information regarding events triggering arteriogenesis (growth of mature arteries) and even less data about maturation and preservation of newly formed vessels. Recent studies from our laboratory have identified a novel class of proline/arginine (PR)-rich peptides may function as a """"""""master switch"""""""" in induction of angiogenesis and arteriogenesis in the setting of """"""""inflammatory"""""""" injury and myocardial ischemia. PR39, the prototypical peptide of this class of molecules, is a macrophage-derived protein capable of stimulating development of functional coronary vasculature in mice hearts. The peptide acts by an unusual mechanism, inhibiting proteasome-mediated degradation of a small number of proteins including hypoxia-inducible factor (HIF)- 1I A and NFKB inhibitor IKBA. In addition, PR39 induces expression of FGF signaling proteins FGF receptor I and syndecan-4. This pattern of activity gives PR39 and related peptides the unusual ability to activate both VEGF (via HIF-1A) and FOF signaling thereby placing them at the center of angiogenic/arteriogenic response. In this grant application we propose to study the functional effects of PR39 induced angiogenesis by examining its effects in ameroid coronary constrictor model and hindlimb ischemia model, to define molecular mechanisms of its action by examining in details it interaction with the proteasomes, and to determine the spectrum of its biological activity by examining the pattern of induced gene expression in various angiogenic models. Additional studies will focus on the role vessel survival in long-term maintenance of effective angiogenic/arteriogenic response. It is hoped that this comprehensive assessment of the novel family of angiogenesis """"""""master switch"""""""" genes may shed new light on regulation of arteriogenic response and provide new avenues for development of therapeutic agents for stimulation of vessel growth.
| Anbanandam, Asokan; Albarado, Diana C; Tirziu, Daniela C et al. (2008) Molecular basis for proline- and arginine-rich peptide inhibition of proteasome. J Mol Biol 384:219-27 |
| Tirziu, Daniela; Moodie, Karen L; Zhuang, Zhen W et al. (2005) Delayed arteriogenesis in hypercholesterolemic mice. Circulation 112:2501-9 |
| Simons, Michael (2004) Integrative signaling in angiogenesis. Mol Cell Biochem 264:99-102 |
| de Muinck, E D; Simons, M (2004) Re-evaluating therapeutic neovascularization. J Mol Cell Cardiol 36:25-32 |
| Khurana, Rohit; Zhuang, Zhenwu; Bhardwaj, Shalini et al. (2004) Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation 110:2436-43 |
| Gaczynska, Maria; Osmulski, Pawel A; Gao, Youhe et al. (2003) Proline- and arginine-rich peptides constitute a novel class of allosteric inhibitors of proteasome activity. Biochemistry 42:8663-70 |
