Release of Cytochrome c, Bax Migration, Bid Cleavage, and Activation of Caspases 2, 3, 6, 7, 8, and 9 during Endothelial Cell Apoptosis

Granville, David J.; Shaw, Janet R; Leong, Simon; Carthy, Christopher M.; Margaron, Philippe; Hunt, David W. C.; McManus, Bruce M.

doi:10.1016/s0002-9440(10)65202-9

Cited by 93 publications

(58 citation statements)

References 22 publications

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“…Western blots on human coronary arteries were performed as described elsewhere (15,16). Briefly, fresh frozen coronary arteries with advanced atherosclerosis and TVD were obtained from the St. Paul's Hospital Cardiovascular Registry.…”

Section: Western Blotmentioning

confidence: 99%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

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Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD).Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle ␣-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0 -5؉/5؉ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle ␣-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.

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Section: Western Blotmentioning

confidence: 99%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

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“…Like the protein kinase inhibitor staurosporine (STS), PDT with mitochondriondamaging photosensitisers induces rapid apoptosis through activation of the mitochondrial pathway of apoptosis. This includes cytochrome c release, caspase activation, PARP cleavage, chromatin condensation and DNA fragmentation (Granville et al, 1998(Granville et al, , 1999bHe et al, 1998;Kessel and Luo, 1998;Kim et al, 1999;Varnes et al, 1999;; reviewed in Oleinick et al (2002)). The induction of apoptosis has also been observed in many tumours at early times following PDT at doses leading to tumour eradication (Zaidi et al, 1993;reviewed in Oleinick et al (2002)).…”

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confidence: 99%

“…Bax undergoes a conformational change (exposure of an epitope detected by the 6A7 antibody) as well as translocation from cytosol to mitochondria immediately or shortly after PDT (Carthy et al, 1999;Granville et al, 1999b). The PDT-induced release of the mitochondrial apoptogenic proteins cytochrome c and Smac/ DIABLO depends on Bax and is blocked in Bax-deficient human prostate cancer DU-145 cells (Usuda et al, 2002).…”

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Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

et al. 2003

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The role of Bax in the release of cytochrome c from mitochondria and the induction of apoptosis has been demonstrated in many systems. Using immunocytochemical staining, we observed that photodynamic therapy (PDT) with the photosensitiser Pc 4 induced Bax translocation from the cytosol to mitochondria, and the release of cytochrome c from mitochondria as early signalling for the intrinsic pathway of apoptosis in human breast cancer MCF-7c3 cells. To test the role of Bax in apoptosis, MCF-7c3 cells were treated with Bax antisense oligonucleotides, which resulted in as much as a 50% inhibition of PDT-induced apoptosis. In the second approach, Bax-negative human prostate cancer DU-145 cells were studied. Following PDT, the hallmarks of apoptosis, including the release of cytochrome c from mitochondria, loss of mitochondrial membrane potential, caspase activation, and chromatin condensation and fragmentation, were completely blocked in these cells. Restoration of Bax expression in DU-145 cells restored apoptosis, indicating that the resistance of DU-145 cells to PDT-induced apoptosis is due to the lack of Bax rather than to another defect in the apoptotic machinery. However, despite the inhibition of apoptosis, the Bax-negative DU-145 cells were as photosensitive as Bax-replete MCF7c3 cells, as determined by clonogenic assay. Thus, for Pc 4-PDT, the commitment to cell death occurs prior to Bax activation.

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“…1 PDT catalyzes the formation of reactive oxygen intermediates and rapidly induces apoptosis in a variety of cell types after light irradiation. [2][3][4][5] …”

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confidence: 99%

“…1 PDT catalyzes the formation of reactive oxygen intermediates and rapidly induces apoptosis in a variety of cell types after light irradiation. [2][3][4][5] In vivo studies have shown that PDT represents a safe, effective method of inhibiting the development of intimal hyperplasia. 6,7 Furthermore, a PDT-mediated reduction in the number of smooth muscle cells (SMCs) occurs along with the prevention of the inflammatory infiltration, aneurysmal dilatation, and development of intimal hyperplasia associated with allograft rejection.…”

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Mitochondrial Release of Apoptosis-Inducing Factor and Cytochrome c During Smooth Muscle Cell Apoptosis

Granville

Cassidy

Ruehlmann

et al. 2001

The American Journal of Pathology

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Photodynamic therapy (PDT) is under investigation for the treatment of intimal hyperplastia in conditions such as atherosclerosis and restenosis. Although smooth muscle cells (SMCs) may be a key target for treatment, the effects of PDT on these cells are poorly characterized. In the present study, apoptosis was induced in primary human aortic SMCs by the combination of the photosensitizer verteporfin and visible light. After PDT, an increase in mitochondrial cytochrome c (cyt c) and apoptosis-inducing factor (AIF) levels were detected in the cytosol immediately and their levels increased steadily up to 2 hours. Cytosolic levels of the pro-apoptotic Bcl-2 family member Bax decreased reciprocally throughout this period, but this change did not occur before cyt c release. Confocal microscopy revealed a diffuse staining pattern of cyt c within apoptotic cells as compared to a distinct mitochondrial staining in normal cells. AIF translocated from mitochondria to the nucleus during the progression of apoptosis. After cyt c release, caspase-9 and caspase-3 processing was visible by 1 hour and caspase-6, -7, and -8 processing was apparent by 2 hours after PDT. In summary, these results demonstrate for the first time the cellular redistribution of mitochondrial AIF during SMC apoptosis, as well as the early release of cyt c and the subsequent activation of multiple caspases during PDT-induced SMC apoptosis. Photodynamic therapy (PDT) is a clinically approved treatment for various types of cancer and the ocular condition known as age-related macular degeneration, the leading cause of blindness in the elderly. PDT is also under investigation for the treatment of other ocular disorders as well as atherosclerosis, restenosis, allograft rejection, and autoimmune disorders. 1 PDT catalyzes the formation of reactive oxygen intermediates and rapidly induces apoptosis in a variety of cell types after light irradiation. [2][3][4][5]

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Release of Cytochrome c, Bax Migration, Bid Cleavage, and Activation of Caspases 2, 3, 6, 7, 8, and 9 during Endothelial Cell Apoptosis

Cited by 93 publications

References 22 publications

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

Mitochondrial Release of Apoptosis-Inducing Factor and Cytochrome c During Smooth Muscle Cell Apoptosis

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