The effects of Probucol, AICAR, and a MK2 inhibitor on human vascular cells, and their possible implementation on drug eluting stents
Abstract
Accounting for 30% of the world population, cardiovascular disease is the most prominent cause of death worldwide. Atherosclerosis is the underlying cause of majority of clinical cardiovascular events, and stents were introduced few decades ago to treat atherosclerotic lesions. To address the restenosis problem of bare metal stents (BMS), drug eluting stents (DES) were introduced. However, recent studies revealed that DESs could result in late in-stent thrombosis (LIST) with the prevalence comparable to that of BMSs. One of the major causes of LIST is that the drugs eluted from the stent are not able to promote endothelial cell (EC) growth while inhibiting smooth muscle cell (SMC) growth, or hyperplasia. Therefore, it is necessary to screen new candidate drugs that would help prevent LIST. In this study, an antioxidant/anticoagulant (Probucol), an AMPK activator (AICAR), and a MK2 inhibitor (MK2i) were tested at various concentrations on human ECs and SMCs in order to assess their effect on cell proliferation, cytokine and chemokine expressions. Results indicated that Probucol promotes EC growth while selectively inhibiting SMC growth. AICAR inhibited growth of both ECs and SMCs, while MK2i had no inhibition effect on EC and SMC growth. Probucol had some anti-inflammatory effect as well, reducing IL-6 and IL-8 levels in ECs. AICAR had no effect on IL-6 and IL-8 levels, whereas MK2i slightly inhibited IL-6 secretion of ECs, but not IL-8. Results also indicated that Probucol potentially lowers intercellular adhesion molecule 1 (ICAM-1), which may reduce the adhesion and penetration of monocytes at the endothelium. Overall, the results suggest that LIST may be prevented by applying one or combination of these chemicals on drug eluting stents. Further in-depth studies are necessary, however this study suggests Probucol may be a great candidate for use in drug eluting stent applications.
Degree
M.S.B.M.E.
Advisors
Park, Purdue University.
Subject Area
Cellular biology|Pharmacy sciences|Biomedical engineering
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