Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model of hindlimb ischemia

Suzuki, Masatoshi; Iso-O, Naoyuki; Takeshita, Satoshi; Tsukamoto, Kazuhisa; Mori, Ichiro; Sato, Tomohide; Ohno, Minoru; Nagai, Ryozo; Ishizaka, Nobukazu

doi:10.1016/s0006-291x(03)00114-1

Cited by 79 publications

(61 citation statements)

References 27 publications

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Section: Introductionmentioning

confidence: 99%

“…One metabolic gene that showed significant up-regulation in KSHV-infected cells was heme oxygenase-1 (HO-1). Given recent evidence implicating HO-1 enzymatic activity in antiapoptotic responses, 36,37 cell proliferation, 38,39 and angiogenesis, [38][39][40][41] we reasoned that up-regulation of this gene by KSHV infection may have important consequences for endothelial cell biology and KS pathophysiology.HOs are responsible for the oxidative cleavage of the heme ring, the rate-limiting step in heme catabolism. 42 Enzymatic degradation of heme releases carbon monoxide (CO), free iron, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase.…”

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confidence: 99%

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Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

McAllister

Hansen

Ruhl

et al. 2004

Blood

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IntroductionKaposi sarcoma-associated herpesvirus (KSHV; also human herpesvirus-8) is implicated in all clinical forms of KS 1,2 as well as the lymphoproliferative disorders primary effusion lymphoma (PEL) 3,4 and multicentric Castleman disease (MCD). 5 Endothelial cells harbor the KSHV genome in vivo, 1,6,7 are permissive for virus infection in vitro, [8][9][10][11] and are thought to be the precursors of spindle cells. [12][13][14][15] We and others have shown that in vitro infection of human dermal microvascular endothelial cells (DMVECs) with KSHV induces a spindle cell morphology and characteristics of a transformed phenotype, including loss of contact inhibition and growth in soft agar. [8][9][10][11] Because explanted KS cells fail to maintain the KSHV genome following serial passage, 16,17 in vitro infection of DMVECs has proved to be an invaluable tool for the study of KSHV pathogenic mechanisms. 18,19 KSHV, like other herpesviruses, has a substantial coding capacity that includes viral genes unique to this human pathogen, genes that share homology with other members of the herpesviridae, as well as genes that appear to have originated in the host genome. 20,21 Of note, at least 3 of these gene products, vFLIP (viral Fas-associating protein with death domain-like interleukin-1␤ [IL-1␤]-converting enzyme [FLICE]-inhibitory protein), viral cyclin (vCYC), and latency-associated nuclear antigen (LANA), are believed to comprise the viral latency expression program and are consistently expressed in all virally infected cells in KS, PEL, and MCD. [22][23][24] The gene product of open reading frame 71 (ORF 71), vFLIP, is thought to play an important role in prevention of apoptotic cell death. 25 The activity of a homolog of cellular cyclin D, vCYC (ORF 72), 26 together with the modulation of cellular transcription wrought by LANA (ORF 73) 27 is thought to be involved in KSHV-induced host cell transformation. Additionally, LANA is indispensable for maintenance of the viral genome. 28 Other gene products, such as viral G-protein-coupled receptor (vGCR) 29,31 are classified as lytic gene products and are expressed in only a minority of cells in vivo. [32][33][34] Although reactivation of KSHV from the latent state and subsequent completion of the viral lytic expression cascade is incompatible with survival of a host cell, lytic gene products are thought to have paracrine influences on both latently infected and uninfected cells and are thus considered vital for lesion development. 35 We have used our previously described in vitro KS model to dissect viral mechanisms of pathogenesis. 18,19 The salient features of our model include recapitulation of KS cell physiology, including spindle cell formation, loss of contact inhibition, and anchoragedependent growth restriction; long-term propagation of predominantly latently infected cells; and the ability to generate ageand passage-matched KSHV-infected and uninfected cultures. 11 This system has been amenable to gene expression profiling by cDNA microarrays and has ...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

McAllister

Hansen

Ruhl

et al. 2004

Blood

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“…12 Noteworthy, the proangiogenic potential of HO-1 has been confirmed in vivo, eg, in the rat hind limb ischemia model, in which overexpression of HO-1 after delivery of cDNA with adenoviral vectors strongly increased synthesis of VEGF and improved neovascularization of the ischemic muscle. 22 Some reports also suggest a correlation between angiogenesis and HO-1 expression in tumors, namely in glioma and pancreatic carcinoma. 16,23 Most studies concerning the role of HO-1 have been performed in the cardiovascular system.…”

mentioning

confidence: 99%

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Waś

Cichoń²,

Smolarczyk³

et al. 2006

The American Journal of Pathology

175

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Heme oxygenases (HOs) catalyze the oxidation of heme to the biologically active products carbon monoxide (CO), biliverdin, and ferrous iron. Two distinct variants of HOs have been described in humans and rodents, each encoded by a different gene: HO-2, which is constitutively expressed, and HO-1, which is potently induced in many cell types by heme, inflammatory cytokines, and oxidative stress-related factors.

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“…Several reports demonstrate HO-1 mediated angiogenesis in various physiological conditions. A recent study documented improvement of blood flow by HO-1 gene transfer in ischemic hind limb, at least in part, via angiogenesis (35). Therefore, the complexity of VEGF biology is paralleled by the emerging complexity of interactions between VEGF ligands and their receptors, and the downstream signaling pathways they mediate in ischemic reperfused myocardium.…”

Section: Discussionmentioning

confidence: 99%

VEGFR1 (Flt-1+/−) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium

Thirunavukkarasu

Juhász

Zhan

et al. 2007

Free Radical Biology and Medicine

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This report demonstrated that mice deficient in Flt-1 failed to establish ischemic preconditioned (PC) mediated cardioprotection in isolated working buffer-perfused ischemic reperfused (IR) hearts compared to wild type (WT) subjected to same PC protocol. Wild type (WT) and Flt-1 +/− mice were divided into four groups: (1) WT IR (2) WT+PC (3) Flt-1 +/− IR (4) Flt-1 +/− +PC. Groups 1 and 3 mice were subjected to 30 min of ischemia followed by 2 hrs of reperfusion and groups 2 and 4 mice were subjected to four episodes of 4-min global ischemia followed by 6 min of reperfusion before ischemia reperfusion. For both wild type and Flt-1 +/− mice, the postischemic functional recovery for the hearts was lower than the baseline, but the recovery for the knockout was less as compared to the WT mice even in preconditioning. The myocardial infarction and apoptosis were higher in Flt-1 +/− compared to wild type I/R. Pronounced inhibition was observed in Flt-1 +/− for p-AKT, peNOS, iNOS and most importantly HO-1 mRNA expression. Results demonstrates that Flt-1 +/− mouse hearts are more susceptible to ischemia reperfusion injury and also documents preconditioning is not as effective as found in WT and therefore suggests the importance of VEGF/Flt-1 signaling in ischemic reperfused myocardium.

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Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model of hindlimb ischemia

Cited by 79 publications

References 27 publications

Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells

Overexpression of Heme Oxygenase-1 in Murine Melanoma

VEGFR1 (Flt-1+/−) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium

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