TY - JOUR
T1 - Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism
AU - Shi, Chongxu
AU - Kim, Tehyung
AU - Steiger, Stefanie
AU - Mulay, Shrikant R.
AU - Klinkhammer, Barbara M.
AU - Baeuerle, Tobias
AU - Melica, Maria Elena
AU - Romagnani, Paola
AU - Moeckel, Diana
AU - Baues, Maike
AU - Yang, Luying
AU - Brouns, Sanne L. N.
AU - Heemskerk, Johan W. M.
AU - Braun, Attila
AU - Lammers, Twan
AU - Boor, Peter
AU - Anders, Hans-Joachim
PY - 2020/4/10
Y1 - 2020/4/10
N2 - Rationale:Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown.Objective:We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure.Methods and Results:C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain-like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity wasConclusions:CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.
AB - Rationale:Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown.Objective:We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure.Methods and Results:C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain-like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity wasConclusions:CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.
KW - acute kidney injury
KW - endothelial cells
KW - extracellular traps
KW - fibrin
KW - necroptosis
KW - NEUTROPHIL EXTRACELLULAR TRAPS
KW - ACUTE KIDNEY INJURY
KW - TRANSCUTANEOUS MEASUREMENT
KW - ATHEROEMBOLIC OCCLUSION
KW - MEDIATES NECROPTOSIS
KW - EMBOLIZATION
KW - ULTRASTRUCTURE
KW - INFLAMMATION
KW - THROMBOSIS
KW - DISEASE
U2 - 10.1161/CIRCRESAHA.119.315625
DO - 10.1161/CIRCRESAHA.119.315625
M3 - Article
C2 - 32089086
SN - 0009-7330
VL - 126
SP - E37-E52
JO - Circulation Research
JF - Circulation Research
IS - 8
ER -