Dimethyl Sulfoxide Inhibits Tissue Factor Expression, Thrombus Formation, and Vascular Smooth Muscle Cell Activation

Abstract

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. Methods and 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-␣ 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 NH 2 kinase (51Ϯ6%; Pϭ0.0005) and p38 (50Ϯ3%; PϽ0.0001) but not p44/42 (PϭNS). 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%; PϽ0.002) and prevented thrombotic occlusion in a mouse carotid artery photochemical injury model. DMSO also inhibited VSMC proliferation (70%; Pϭ0.005) and migration (77%; Pϭ0.0001) 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.

DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

“…DMSO was previously suggested to inhibit platelet activation; however, this was postulated only indirectly and without any molecular insights [6,8]. In this study, we for the first time can clearly demonstrate that DMSO inhibits platelet adherence and platelet aggregation which are essential steps for the physiological and pathophysiological formation of a stable occlusive thrombus [24].…”

“…Furthermore, in previous in vitro studies we have shown that DMSO concentrations up to 1% are not toxic for human endothelial cells, smooth muscle cells and peripheral blood monocytes [6].…”

“…In line with this, we recently showed that drugs released from DES enhance tissue factor (TF), a key trigger for thrombosis and thus could play a paradoxical role in eliciting stent thrombosis [29,32]. In this context, DMSO could represent an interesting alternative drug which not only inhibits human vascular smooth muscle cell (HVSMC) proliferation, but also prevents TF expression and thrombus formation in vivo [6].…”

“…Arterial thrombosis is the crucial event in a large number of cardiovascular conditions such as acute coronary syndromes (ACS) [6,19]. Even though coronary bare metal stents (BMS) and drug-eluting stent (DES) implantation greatly improved prognosis of ACS patients, acute and sub-acute stent thrombosis still remain a serious concern [4,5,14,15,17,20,31,34].…”

“…In light of its previously reported properties including inhibition of HVSMC proliferation and TF-mediated thrombosis [6,8], we investigated whether DMSO inhibits platelet activation and thus exerts its strong anti-thrombotic properties via a combined inhibitory effect.…”