Therapeutic angiogenesis in cardiovascular disease

Simons, Michael; Ware, J. Anthony

doi:10.1038/nrd1226

Cited by 291 publications

(205 citation statements)

References 51 publications

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“…Our findings correspond nicely with previous studies when VEGF was bolus injected or systemic delivered: applied VEGF showed relatively low efficiency due to rapid clearance from the target site, and edema can result from VEGF's tendency to increase vascular permeability. Furthermore, high local levels of VEGF can reduce up-regulated formation of supernumerary but malformed vessels in hemangioma-like assemblies (31)(32)(33). A possible explanation for our favorable result might be that HIF-1␣⌬ODD not only induces a proangiogenic stimulus mediated by a single growth factor such as delivered by a protein-based therapy but also initiates the entire strictly regulated and equilibrated cascade of events leading to formation of more mature vascular structures.…”

Section: Discussionmentioning

confidence: 86%

Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1α variant for local induction of angiogenesis

Trentin

Hall

Wechsler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

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Section: Discussionmentioning

confidence: 86%

Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1α variant for local induction of angiogenesis

Trentin

Hall

Wechsler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

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“…In contrast, it has beneficial effects on ischemic injury to the heart and brain, suggesting that a low molecular weight activa- tor of HIF-1␣ and its target genes could provide a novel treatment for stroke and myocardial infarction (31,32). The beneficial effects of HIF-1 are mostly mediated by its target genes, the most prominent of which are EPO and VEGF, which are considered major mediators of the protective effect of hypoxic preconditioning (33)(34)(35)(36). Pre-exposure of wild-type mice to brief hypoxia resulted in protection of isolated hearts against ischemia-reperfusion injury 24 h later, and the cardiac protection induced by this preconditioning program was lost in HIF-1␣ ϩ/Ϫ mice (37).…”

Section: Discussionmentioning

confidence: 99%

Clioquinol, a Cu(II)/Zn(II) Chelator, Inhibits Both Ubiquitination and Asparagine Hydroxylation of Hypoxia-inducible Factor-1α, Leading to Expression of Vascular Endothelial Growth Factor and Erythropoietin in Normoxic Cells

Choi

Park

et al. 2006

Journal of Biological Chemistry

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Hypoxia-inducible factor 1 (HIF-1) 3 is a key regulator of hypoxic adaptation that functions by activating the transcription of several genes involved in angiogenesis, erythropoiesis, and glycolysis (1, 2). It consists of two subunits; HIF-1␣ is rapidly degraded under normoxic condition by the ubiquitin-proteasome system, whereas HIF-1␤ is stable. Under normoxic conditions the proline 564 and/or 402 residues of HIF-1␣ are hydroxylated by HIF-1␣-specific prolyl-4 hydroxylases (PHDs), which need O 2 , ␣-ketoglutarate, vitamin C, and Fe(II) (3-6). The hydroxylated prolines interact with von Hippel-Lindau (VHL) protein, a component of E3 ubiquitin ligase, and the HIF-1␣ is ubiquitinated by the VCB E3 ubiquitin-ligase complex, consisting of VHL protein, ElonginB, ElonginC, Cul2, and Rbx1 (7,8). In hypoxic conditions, proline hydroxylation decreases and HIF-1␣ accumulates. Oxygen molecules inhibit not only the stabilization of HIF-1␣ but also its transactivation activity, because the protein, factor-inhibiting HIF-1␣ (FIH-1), catalyzes hydroxylation of its asparagine residue using O 2 , ␣-ketoglutarate, vitamin C, and Fe(II). Hydroxylation of this asparagine residue in the transactivation domain of HIF-1␣ prevents it from recruiting its coactivator, cAMP-response element-binding protein (CBP) (3, 9).Thus, activation of HIF-1␣ is censored by two systems, proline hydroxylation and asparagine hydroxylation. HIF-1␣ and its targets, such as EPO and VEGF, are being evaluated as therapeutic agents for cerebral and myocardial infarctions, and a small lipophilic HIF-1␣-activating compound is being sought as a treatment for these diseases. However, to generate fully functional HIF-1␣, a putative HIF-1␣ activator should suppress both proline hydroxylation-dependent ubiquitination and asparagine hydroxylation.We showed previously that the zinc chelator N,N,NЈ,NЈ-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) enhances the activity of PHD2 but that the level of HIF-1␣ protein does not fall because TPEN also inhibits its ubiquitination. Because TPEN does not prevent FIH-1 from hydroxylating the asparagine residue of HIF-1␣, it leads the accumulation of nonfunctional HIF-1␣ (10, 11). Here, we report that another zinc chelator, Clioquinol, which has relatively low affinity but high selectivity for Zn(II) and Cu(II), has a different effect on the activity of HIF-1␣. Both TPEN and Clioquinol inhibit ubiquitination of HIF-1␣ and cause its accumulation. However, in contrast to TPEN, Clioquinol prevents FIH-1 from hydroxylating HIF-1␣. It therefore stabilizes functional HIF-1␣, leading to expression of its target genes in normoxic cells.Clioquinol has been used in Alzheimer, Parkinson, and Huntington diseases as a Cu(II)-and Zn(II) chelator that reverses Zn(II)-or Cu(II)-induced metalloprotein precipitation (12). It

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“…In contrast, revascularization and collateral circulation is a desired process in the ischemic heart muscle and limb and is becoming the therapeutic goal [90]. However, a principle reason for the failure of angiogenic therapy could be the decreased effectiveness of growth factors due to endothelial dysfunction [91].…”

Section: Resistin and Atherosclerosismentioning

confidence: 99%

The role of resistin as a regulator of inflammation: Implications for various human pathologies

Filková

Haluzı́k

Šenolt

2009

Clinical Immunology

375

297

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Therapeutic angiogenesis in cardiovascular disease

Cited by 291 publications

References 51 publications

Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1α variant for local induction of angiogenesis

Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1α variant for local induction of angiogenesis

Clioquinol, a Cu(II)/Zn(II) Chelator, Inhibits Both Ubiquitination and Asparagine Hydroxylation of Hypoxia-inducible Factor-1α, Leading to Expression of Vascular Endothelial Growth Factor and Erythropoietin in Normoxic Cells

The role of resistin as a regulator of inflammation: Implications for various human pathologies

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