TY - JOUR
T1 - Differential cytotoxic actions of Shiga toxin 1 and Shiga toxin 2 on microvascular and macrovascular endothelial cells
AU - Bauwens, Andreas
AU - Bielaszewska, Martina
AU - Kemper, Björn
AU - Langehanenberg, Patrik
AU - Von Bally, Gert
AU - Reichelt, Rudolf
AU - Mulac, Dennis
AU - Humpf, Hans Ulrich
AU - Friedrich, Alexander W.
AU - Kim, Kwang S.
AU - Karch, Helge
AU - Müthing, Johannes
PY - 2011/3
Y1 - 2011/3
N2 - Shiga toxin (Stx)-mediated injury to vascular endothelial cells in the kidneys, brain and other organs underlies the pathogenesis of haemolytic uraemic syndrome (HUS) caused by enterohaemorrhagic Escherichia coli (EHEC). We present a direct and comprehensive comparison of cellular injury induced by the two major Stx types, Stx1 and Stx2, in human brain microvascular endothelial cells (HBMECs) and EA.hy 926 macrovascular endothelial cells. Scanning electron microscopy of micro-carrier-based cell cultures, digital holographic microscopy of living single cells, and quantitative apoptosis/necrosis assays demonstrate that Stx1 causes both necrosis and apoptosis, whereas Stx2 induces almost exclusively apoptosis in both cell lines. Moreover, microvascular and macrovascular endothelial cells have different susceptibilities to the toxins: EA.hy 926 cells are slightly, but significantly (∼ 10 times) more susceptible to Stx1, whereas HBMECs are strikingly (≥ 1,000 times) more susceptible to Stx2. These findings have implications in the pathogenesis of HUS, and suggest the existence of yet to be delineated Stx type-specific mechanisms of endothelial cell injury beyond inhibition of protein biosynthesis.
AB - Shiga toxin (Stx)-mediated injury to vascular endothelial cells in the kidneys, brain and other organs underlies the pathogenesis of haemolytic uraemic syndrome (HUS) caused by enterohaemorrhagic Escherichia coli (EHEC). We present a direct and comprehensive comparison of cellular injury induced by the two major Stx types, Stx1 and Stx2, in human brain microvascular endothelial cells (HBMECs) and EA.hy 926 macrovascular endothelial cells. Scanning electron microscopy of micro-carrier-based cell cultures, digital holographic microscopy of living single cells, and quantitative apoptosis/necrosis assays demonstrate that Stx1 causes both necrosis and apoptosis, whereas Stx2 induces almost exclusively apoptosis in both cell lines. Moreover, microvascular and macrovascular endothelial cells have different susceptibilities to the toxins: EA.hy 926 cells are slightly, but significantly (∼ 10 times) more susceptible to Stx1, whereas HBMECs are strikingly (≥ 1,000 times) more susceptible to Stx2. These findings have implications in the pathogenesis of HUS, and suggest the existence of yet to be delineated Stx type-specific mechanisms of endothelial cell injury beyond inhibition of protein biosynthesis.
KW - Apoptosis
KW - Endothelial cells
KW - Enterohaemorrhagic e. Coli
KW - Necrosis
KW - Shiga toxin
KW - Single cell analysis
UR - http://www.scopus.com/inward/record.url?scp=79952531667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952531667&partnerID=8YFLogxK
U2 - 10.1160/TH10-02-0140
DO - 10.1160/TH10-02-0140
M3 - Article
C2 - 21136010
AN - SCOPUS:79952531667
SN - 0340-6245
VL - 105
SP - 515
EP - 528
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
IS - 3
ER -