American Heart Association Grant-in-Aid
In collaboration with Dr. Michael Hoffmann’s lab.
Atherosclerosis is the leading cause of death in the United States. Unfortunately, interventions designed to treat atherosclerosis frequently fail because of restenosis, which is typified by re-narrowing of the arterial lumen. The pathology of restenosis is primarily intimal hyperplasia and central to this process is smooth muscle cell (SMC) proliferation. Currently in clinical practice, drug-eluting stents with Rapamycin and Paclitaxel, both inhibitors of SMC proliferation, have been somewhat effective in reducing restenosis in the coronary circulation. Unfortunately, both drugs inhibit endothelial cell (EC) proliferation and migration and thus prevent the critically important process of reestablishing the vessels protective endothelial lining which is often denuded as a byproduct of vascular reconstruction. Thus, there is an unmet medical need for highly selective drugs that can potently inhibit SMC proliferation but have only a minimal effect on proliferation of ECs. We will use a high throughput screening (HTS) strategy and primary human cells to discover drugs that selectively and potently retard SMC proliferation while leaving the growth of ECs unaffected. We have developed a reproducible HTS setting, using which we have screened 447 compounds in the NIH Clinical Collection for SMC and EC proliferation at the UW-Madison Small Molecule Screening and Synthesis Facility. We have identified 11 hits that inhibited SMC proliferation more than 50% with one having a minor effect on ECs. We propose to scale up screening against larger libraries (total ~35,000 compounds) including the Prestwick Library which contains 1200 FDA-approved drugs. Positive hits will be further evaluated by comparing concentration-response curves for human SMCs versus ECs and selecting compounds that preferentially inhibit SMCs. Finally, a few compounds will be evaluated using an established rat model of restenosis for their in vivo potential to inhibit restenosis but preserve reendothelialization. Our goal is to identify lead compounds for a new generation of anti-restenosis drugs that will improve the long-term outcomes of the millions of people each year who undergo interventions for atherosclerosis.