Our research aims to uncover the molecular mechanisms driving atherosclerosis, a chronic inflammatory disease that leads to major adverse cardiovascular events (MACE), such as myocardial infarction (MI) and stroke—two of the leading causes of death globally. By leveraging advanced preclinical mouse models that integrate cell-specific lineage tracing with gene knockouts, we strive to bridge basic science and clinical application by identifying and validating novel therapeutic targets that enhance atherosclerotic plaque stability, ultimately reducing the incidence of MACE and improving patient survival.

Specific projects in our lab include:

1.) We recently showed that treatment of our novel SR-BI^ΔCT/ΔCT/Ldlr^-/- mice (which are prone to diet-inducible MI and stroke) with an inhibitor of myeloperoxidase (MPO) markedly reduced spontaneous plaque rupture (SPR), MI, and stroke as well as improved survival when administered throughout WD feeding in a prevention model. The concentration of MPO inhibitor used in these studies inhibits 90% of extracellular MPO activity (which drives oxidative tissue damage) while minimally affecting intragranular MPO activity (which is crucial for neutrophil microbial killing) and thus may pose less risk to innate immunity. This highlights the therapeutic potential of targeting MPO in human cardiovascular disease. Our future studies will focus on testing the hypothesis that plasma MPO levels and MPO-oxidized extracellular matrix (ECM) peptides can serve as biomarkers for predicting imminent plaque rupture. We will also investigate whether selective inhibition of MPO activity can serve as an effective intervention after advanced lesion formation while preserving innate immune function.

2.) Our lab has demonstrated that radiation therapy compromises mouse atherosclerotic plaque stability by inhibiting smooth muscle cell investment into the plaque. We are currently investigating the underlying mechanisms driving this effect. Cancer survivors are known to have an elevated risk of cardiovascular events. Future directions will examine whether these findings translate to human atherosclerotic disease and will determine whether other cancer therapies, such as chemotherapy and small-molecule inhibitors, similarly reduce plaque stability through related pathways.