Bcl-xL Gene Transfer Inhibits Bax Translocation and Prolongs Cardiac Cold Preservation Time in Rats

Abstract

Background-Apoptosis is an important cause of early graft loss after heart transplantation. Bcl-xL was reported to protect the heart against normothermic ischemia and reperfusion injury. In this study, we determined whether overexpression of Bcl-xL could inhibit tissue injury resulting from prolonged cold preservation followed by warm reperfusion of heart transplants. Methods and Results-Lewis rat hearts were transduced with an adenovirus vector harboring Bcl-xL cDNA (AxCAhBclxL) 4 days before collection of tissue. After preservation in University of Wisconsin solution at 4°C for 24 hours, the heart was either perfused with a Langendorff device ex vivo or used for heterotopic heart transplantation in vivo. Bcl-xL gene transfer significantly reduced the infarct size (23.0Ϯ2.6% versus 47.7Ϯ7.0% in saline control and 48.6Ϯ6.1% in vector control, PϽ0.01) after 2-hour reperfusion at 37°C with the Langendorff device and significantly decreased creatine kinase release (0.82Ϯ0.27 IU, versus 1.57Ϯ0.33 and 1.50Ϯ0.37 IU in saline and vector controls, respectively; PϽ0.05). In heart transplantation, overexpresson of Bcl-xL inhibited Bax translocation from the cytosol to the mitochondria, resulting in decreased cytochrome c release from the mitochondria; it also significantly decreased cardiac cell apoptosis and improved graft survival rate after long cold preservation, followed by warm reperfusion. Conclusions-Bcl-xL

Cell Death and Adenosine Triphosphate

“…Bcl-xL belongs to the large Bcl-2 family and has been reported to inhibit Bax translocation to the mitochondria and to reduce cytochrome c release, thereby interrupting the apoptotic cascade and reducing the number of cells dying by apoptosis. 2,3 This is precisely what Huang et al 1 have shown-namely, that inhibition of the apoptotic pathway can partially prevent the deleterious effects of long-term ischemia by reducing the rate of apoptosis. In addition, these authors show that "infarct size" was reduced in treated hearts and that the rate of polymorphonuclear cell infiltration was minimal as compared with hearts without gene transfer.…”

“…6 In addition, a third type of cellular demise has been described, autophagic cell death, but this may not be of great importance in the present animal model because it occurs mostly in tissue exhibiting chronic degeneration, such as Alzheimer's disease in the brain and failure of the human heart. 7,8 Huang et al 1 showed that Bcl-xL gene transfer prevented Bax loss from the cytosol and decreased cytochrome c release from the mitochondria, whereas Bax was translocated from the cytosol to the mitochondria and caused massive cytochrome c release in untreated hearts. 1 These data are in line with accumulating evidence suggesting an intimate interrelationship of apoptosis and mitochondrial function that occurs at the interface between Bcl-2 family proteins and the outer mitochondrial membrane protein, namely voltage-dependent anion channel (VDAC).…”

“…T he inhibition of cell death lies at the heart of the interesting publication in this issue of Circulation by Huang et al 1 The authors' major message is that Bcl-xL gene transfer prolongs the cold preservation time of rat hearts destined for transplantation. Bcl-xL belongs to the large Bcl-2 family and has been reported to inhibit Bax translocation to the mitochondria and to reduce cytochrome c release, thereby interrupting the apoptotic cascade and reducing the number of cells dying by apoptosis.…”

GATA-3 transduces survival signals in osteoblasts through upregulation of bcl-x L gene expression

“…A previous study showed that overexpression of the bcl-x L gene inhibits Bax translocation and cytochrome C release and prevents cardiac cells from apoptosis. (26) Thus NO preconditioning can induce expression of the bcl-x L gene and its translocation, leading to protection against oxidative stress-caused osteoblast insults. GATA-3 mediates NO preconditioning-caused osteoblast protection.…”

“…(25) In ischemia-reperfusion-induced heart injury, overexpression of the bcl-x L gene was shown to suppress Bax translocation, leading to a reduction in cytochrome C release and cardiac cell apoptosis. (26) Thus expression of the bcl-x L gene is regulated by various stimuli, and its intracellular levels drive cells to undergo survival or apoptosis. A previous study reported that GATA-DNA-binding elements are found in the 5'-end promoter region of the bcl-x L gene.…”