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(American Journal of Pathology. 2001;159:305-311.)
© 2001 American Society for Investigative Pathology

Regular Articles

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

David J. Granville^*, Brighid A. Cassidy^*, Dietrich O. Ruehlmann, Jonathan C. Choy^*, Catherine Brenner, Guido Kroemer^¶, Cornelis van Breemen, Philippe Margaron, David W. Hunt and Bruce M. McManus^*

From the Department of Pathology and Laboratory Medicine,^*
University of British Columbia McDonald Research Laboratories/The iCAPTURE Centre, St. Paul’s Hospital/Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada; QLT Inc.,
Vancouver, British Columbia, Canada; the Department of Pharmacology and Therapeutics,
University of British Columbia, Vancouver, British Columbia, Canada; the Centre National de la Recherche Scientifique,
Université de Technologie de Compiègne, Compiègne, France; and the Centre National de la Recherche Scientifique,^¶
Institut Gustave Roussy, Villejuif, France

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.

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