Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents.
BACKGROUND
Subacute stent thrombosis is a major clinical concern, and the search for new molecules to cover stents remains important. Dimethyl sulfoxide (DMSO) is used for preservation of hematopoietic progenitor cells and is infused into patients undergoing bone marrow transplantation. Despite its intravenous application, the impact of DMSO on vascular cells has not been assessed.


RESULTS
In human endothelial cells, monocytes, and vascular smooth muscle cells (VSMC), DMSO inhibited tissue factor (TF) expression and activity in response to tumor necrosis factor-alpha or thrombin in a concentration-dependent manner. DMSO did not exert any toxic effects as assessed by phase-contrast microscopy, trypan blue exclusion, and lactate dehydrogenase release. Real-time polymerase chain reaction revealed that inhibition of TF expression occurred at the mRNA level. This effect was mediated by reduced activation of the mitogen-activated protein kinases c-Jun terminal NH2 kinase (51+/-6%; P=0.0005) and p38 (50+/-3%; P<0.0001) but not p44/42 (P=NS). In contrast to TF, DMSO did not affect expression of TF pathway inhibitor or plasminogen activator inhibitor-1. In vivo, DMSO treatment suppressed TF activity (41%; P<0.002) and prevented thrombotic occlusion in a mouse carotid artery photochemical injury model. DMSO also inhibited VSMC proliferation (70%; P=0.005) and migration (77%; P=0.0001) in a concentration-dependent manner; moreover, it prevented rapamycin and paclitaxel-induced upregulation of TF expression.


CONCLUSIONS
DMSO suppresses TF expression and activity, as well as thrombus formation; in addition, it inhibits VSMC proliferation and migration. Given its routine use in modern clinical practice, we propose DMSO as a novel strategy for coating drug-eluting stents and treating acute coronary syndromes.
Camici
Giovanni G
GG
Cardiovascular Research, Physiology Institute, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Steffel
Jan
J
Akhmedov
Alexander
A
Schafer
Nicola
N
Baldinger
Jeannette
J
Schulz
Urs
U
Shojaati
Kushiar
K
Matter
Christian M
CM
Yang
Zhihong
Z
Lüscher
Thomas F
TF
Tanner
Felix C
FC
D000818:Animals; D002341:Carotid Artery Thrombosis; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
D013925:Thromboplastin; D004121:Dimethyl Sulfoxide