Adenoviral Human BCL-2 Transgene Expression Attenuates Early Donor Cell Death After Cardiomyoblast Transplantation Into Ischemic Rat Hearts

Kutschka, Ingo; Kofidis, Theo; Chen, Ian Y.; Degenfeld, Georges von; Zwierzchoniewska, Monika; Hoyt, Grant; Arai, Takayasu; Lebl, Darren R.; Hendry, Stephen L.; Sheikh, Ahmad Y.; Cooke, David T.; Connolly, Andrew J.; Blau, Helen M.; Gambhir, Sanjiv S.; Robbins, Robert C.

doi:10.1161/circulationaha.105.001370

Cited by 93 publications

(43 citation statements)

References 21 publications

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“…To further investigate mitochondrial mechanisms potentially involved, which may modulate apoptosis, we measured the antiapoptotic protein Bcl-2 (35), which constitutes a pivotal regulator of mitochondrial apoptosis (36). A recent study strengthens the emergent role for Bcl-2 in protecting cardiac cells against death, including apoptosis (37). Although others have found a reduction in the antiapoptotic protein Bcl-2 in chronic doxorubicin-induced cardiomyopathy (34), we found in the acute situation of our model no regulation of this protein at all.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

et al. 2009

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Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatintreated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, À29%; dp/dtmax, À45%; cardiac output, À68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor A and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and antiinflammatory effects. [Cancer Res 2009;69(2):695-9]

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Section: Discussionmentioning

confidence: 99%

Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

et al. 2009

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“…Approaches to boosting cell survival for grafting applications in different tissues and organ systems have also been evaluated. Overexpression of Bcl-2 has been shown to improve survival of endothelial [81,82] and cardiac [83] cells implanted subcutaneously. Caspase inhibition provided to cultured cells, and delivered systemically after injection enhances survival of islet cells [84] and dopaminergic neurons [85,86].…”

Section: Strategies To Increase Cell Survivalmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

364

294

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Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them.Most anti-death studies use histology to assess engraftment, which is time-and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enyzmatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.

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“…Growth factors continuously stimulate tyrosine kinase activity to suppress the proapoptotic and BH3-only family members, and thus prevent initiation of apoptosis (17,18). Enforced expression of the 26-kDa BCL2 antiapoptotic protein has been reported to result in enhanced survival and proliferation in several different systems (16,19,20). We demonstrated that mouse embryonic stem-cell (mESC) lines expressing the human BCL2 transgene could self-renew continuously under serum-free and feeder cell-free conditions (21), and improved efforts to identify and isolate mouse ES-derived HSC (22).…”

mentioning

confidence: 99%

Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors

Ardehali

Inlay

Ali

et al. 2011

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

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The promise of pluripotent stem cells as a research and therapeutic tool is partly undermined by the technical challenges of generating and maintaining these cells in culture. Human embryonic stem cells (hESCs) are exquisitely sensitive to culture conditions, and require constant signaling by growth factors and cell-cell and cellmatrix interactions to prevent apoptosis, senescence, and differentiation. Previous work from our laboratory demonstrated that overexpression of the prosurvival gene BCL2 in mouse embryonic stem cells overrode the requirement of serum factors and feeder cells to maintain mESCs in culture. To determine whether this prosurvival gene could similarly protect hESCs, we generated hESC lines that constitutively or inducibly express BCL2. We find that BCL2 overexpression significantly decreases dissociation-induced apoptosis, resulting in enhanced colony formation from sorted single cells, and enhanced embryoid body formation. In addition, BCL2-hESCs exhibit normal growth in the absence of serum, but require basic fibroblast growth factor to remain undifferentiated. Furthermore, they maintain their pluripotency markers, form teratomas in vivo, and differentiate into all three germ layers. Our data suggest that the BCL2 signaling pathway plays an important role in inhibiting hESC apoptosis, such that its overexpression in hESCs offers both a survival benefit in conditions of stress by resisting apoptosis and obviates the requirement for serum or a feeder layer for maintenance.embryonic stem cell survival | viability

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Adenoviral Human BCL-2 Transgene Expression Attenuates Early Donor Cell Death After Cardiomyoblast Transplantation Into Ischemic Rat Hearts

Cited by 93 publications

References 21 publications

Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

Systems approaches to preventing transplanted cell death in cardiac repair

Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors

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