Molecular switches for regulating therapeutic genes

Webster, Keith A.

doi:10.1038/sj.gt.3300959

Cited by 9 publications

(5 citation statements)

References 10 publications

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“…Incorporation of hypoxia-responsive, oxidative stress, and silencer elements in the transgene promoter that specifically activate gene expression during ischemia or reperfusion may help to accomplish this and perhaps create a feasible, safe method for delivering IGF-1 genes to diseased hearts. [37][38][39] …”

Section: Discussionmentioning

confidence: 99%

Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1

Yamashita

Kajstura

Discher

et al. 2001

Circulation Research

139

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Abstract-Hearts of wild-type and insulin-like growth factor-1 overexpressing (Igf-1 ϩ/Ϫ ) transgenic mice were subjected to Langendorff perfusions and progressive periods of ischemia followed by reperfusion. Apoptosis was measured by DNA nucleosomal cleavage and a hairpin probe labeling assay to detect single-base overhang. Transgenic hearts subjected to 20 minutes of ischemia and 4 hours of reperfusion (I/R) sustained a rate of apoptosis of 1.8Ϯ0.3% compared with 4.6Ϯ1.1% for wild-type controls (nϭ4; PϽ0.03). Phosphorylation of the protein kinase Akt/protein kinase B was elevated 6.2-fold in transgenic hearts at baseline and increased another 4.4-fold within 10 minutes of reperfusion, remaining elevated for up to 2 hours. I/R activated Akt in wild-type hearts but to a lesser extent (1.6Ϯ0.3-fold). Pretreatment of transgenic hearts with wortmannin immediately before and during ischemia eliminated reperfusionmediated activation of Akt and neutralized the resistance to apoptosis. The stress-activated kinase p38 was also activated during ischemia and reperfusion in both wild-type and transgenic hearts. Perfusion with the p38 inhibitor SB203580 (10 mol/L) blocked both p38 activation and phosphorylation of Akt and differentially modulated apoptosis in wild-type and transgenic hearts. Pretreatment with SB203580 reduced apoptosis in wild-type hearts but increased apoptosis in transgenic hearts. These results demonstrate that Akt phosphorylation during I/R is modulated by IGF-1 and prevents apoptosis in hearts that overexpress the IGF-1 transgene. (Circ Res. 2001;88:609-614.) Key Words: ischemia Ⅲ hypoxia Ⅲ phosphoinositol-3Ј-kinase Ⅲ p38 mitogen-activated protein kinase Ⅲ SB203580 P rotective and antiapoptotic properties of insulin-like growth factor-1 (IGF-1) have been demonstrated in different models of myocardial ischemia and infarction 1-4 as well as in isolated cardiac myocytes subjected to ischemic or oxidative stress. 5,6 IGF-1 stimulates the phosphoinositol-3Ј (PI3)-kinase pathway, producing phosphoinositides that promote activation of the kinase Akt. 7,8 Activated Akt kinase plays a central role in suppressing apoptosis by modulating the activities of Bcl-2 family proteins, 9 caspase 9, 10 and Fas ligand. 11 Transfer of mutationally activated PI3-kinase and Akt genes has been shown to prevent apoptosis of cardiac myocytes in vitro, 6 and activated Akt delivered by an adenovirus vector reduced apoptosis in the intact heart subjected to ischemia and reperfusion (I/R). 4 We previously reported that Igf-1 ϩ/Ϫ transgenic mice overexpressing IGF-1 had reduced rates of necrosis and apoptosis after myocardial infarction caused by coronary artery ligation. 3 The same hearts were also resistant to necrosis but not apoptosis caused by nonocclusive coronary artery constriction. 12 Other work has shown that the endogenous PI3-kinase pathway is activated in the postinfarcted myocardium, where it may contribute to cell survival and hypertrophy. [13][14][15] Regulation of the endogenous PI3-kinase pathway during I/R has not b...

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Section: Discussionmentioning

confidence: 99%

Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1

Yamashita

Kajstura

Discher

et al. 2001

Circulation Research

139

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“…It seems possible that sustained expression of VEGF, possibly using an AAV delivery system with VEGF expression regulated by a hypoxia (HIF-1) responsive promoter, will promote stable conducting vessels. 4,22 Indeed, a recent report indicated that sustained VEGF expression supported by AAV-mediated delivery induced arteriogenesis in the rat hindlimb. 23 In conclusion, angiogenesis in the ischemic hindlimb in response to Ad-VEGF injection is confined to the period of VEGF expression that occurs in the first week of gene delivery.…”

Section: Adenoviral-vegf-mediated Angiogenesis Mj Gounis Et Almentioning

confidence: 99%

Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle

Graham

et al. 2005

Gene Ther

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“…A key question regarding timing of transgene expression will be whether endostatin expression ceases once the pathology has subsided. Cell specific and hypoxia-regulated vectors have been shown to switch off in other systems including heart 36,62 and cancer. 63,64 Given the tight correspondence between tissue hypoxia and the induction, maintenance, and termination of HIF signaling, it is anticipated that the activity of REG-Endo will closely correlate with retinal hypoxia.…”

Section: Hre-regulated Switch In Normoxiamentioning

confidence: 99%

A Hypoxia-Responsive Glial Cell-Specific Gene Therapy Vector for Targeting Retinal Neovascularization

Biswal

et al. 2014

Investigative Ophthalmology & Visual Science

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Molecular switches for regulating therapeutic genes

Cited by 9 publications

References 10 publications

Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1

Reperfusion-Activated Akt Kinase Prevents Apoptosis in Transgenic Mouse Hearts Overexpressing Insulin-Like Growth Factor-1

Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle

A Hypoxia-Responsive Glial Cell-Specific Gene Therapy Vector for Targeting Retinal Neovascularization

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