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Eur J Vasc Endovasc Surg. 2014 Sep;48(3):248-57. doi: 10.1016/j.ejvs.2014.06.038. Epub 2014 Jul 22.

Activation of the proapoptotic unfolded protein response in plaques of the human carotid artery.

Author information

1
Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany. Electronic address: bernhard.dorweiler@unimedizin-mainz.de.
2
Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
3
Center for Thrombosis and Hemostasis, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.

Abstract

OBJECTIVE:

To analyze expression of keystone markers of apoptosis and the proapoptotic signaling pathway "unfolded protein response" (UPR) in rupture-prone plaques of the human carotid artery.

METHODS:

Plaque specimens were obtained during endarterectomy for high-grade carotid stenosis, and were formalin-fixed. Ten specimens were identified that exhibited criteria of advanced rupture-prone atherosclerotic plaques, and histological and immunohistological analysis of markers of apoptosis (cleaved Caspase-3, TUNEL) and UPR (KDEL, ATF3, CHOP, CHAC-1) was performed. In addition, co-localization of apoptosis and UPR-activation was assessed by double-immunohistochemistry.

RESULTS:

The mean size of the necrotic core was 44 ± 7% and the mean minimum/representative thicknesses of the fibrous cap were 129 ± 39 μm/280 ± 60 μm, respectively. Each specimen fulfilled at least two of the criteria for rupture-prone plaques. Semi-quantitative analysis of immunohistochemistry showed a significant increase in cleaved Caspase-3-positive (1923 ± 93 cells/mm(2)) and TUNEL-positive cells (1387 ± 66 cells/mm(2)) when compared with control tissue. Furthermore, expression of UPR-markers KDEL, AFT3 and CHOP was significantly increased (1175 ± 40 cells/mm(2), 1971 ± 69 cells/mm(2) and 2173 ± 120 cells/mm(2), respectively). Co-localization of UPR-activation with apoptosis was confirmed by double-immunohistochemistry, and lesional macrophages were identified as the primary cell-type involved.

CONCLUSION:

For the first time, activation of the proapoptotic signaling pathway UPR has been identified in advanced rupture-prone plaques of the human carotid artery. This provides additional evidence for adding UPR to the potential targets for controlling plaque apoptosis and thereby preventing plaque progression/rupture.

KEYWORDS:

Apoptosis; Atherosclerotic plaque; Carotid stenosis; Immunohistochemistry; Unfolded protein response

PMID:
25060744
DOI:
10.1016/j.ejvs.2014.06.038
[Indexed for MEDLINE]
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