Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity.
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 alpha-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 alpha-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.
The iCAPTUR4E Centre/UBC McDonald Research Laboratories, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada.
Jonathan C
JC
Choy
Paul C
PC
McDonald
Agripina C
AC
Suarez
Vivian H Y
VH
Hung
Janet E
JE
Wilson
Bruce M
BM
McManus
David J
DJ
Granville
D017209:Apoptosis; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D005487:Foam Cells / Q000201:enzymology / Q000473:pathology; D053804:Granzymes; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D016377:Organ Transplantation / Q000009:adverse effects; D011183:Postoperative Complications; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014652:Vascular Diseases / Q000201:enzymology* / Q000209:etiology
D012333:RNA, Messenger; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases