Downregulation of GSK-3β Expression via Ultrasound-Targeted Microbubble Destruction Enhances Atherosclerotic Plaque Stability in New Zealand Rabbits

Abstract

Accumulating evidence suggests that atherosclerosis (AS) is the underlying cause of vascular diseases, including heart disease and stroke. Ultrasound-targeted microbubble destruction (UTMD) technology provides a tolerable, efficient and effective system for drug delivery and gene transfection, which has broad application prospects in the treatment of AS. In addition, glycogen synthase kinase (GSK)-3β has been implicated as a potentially valuable therapeutic agent for AS treatment; however, the specific molecular mechanisms remain unknown. Therefore, this study was conducted to explore the effect of downregulation of GSK-3β expression via UTMD on atherosclerotic plaque stability. We established a THP-1 macrophage-derived foam cell model in vitro and an atherosclerotic plaque model in the right common carotid artery of New Zealand rabbits. We determined levels of the relevant vulnerable plaque stability elements. The results indicate that GSK-3β was upregulated in the foam cells and in atherosclerotic rabbits. Downregulation of GSK-3β expression by UTMD suppressed vulnerable plaque factors and inflammation in vitro and in vivo, changed the cytoskeleton of the foam cells in vitro, increased Young's modulus and decreased the peak intensity of atherosclerotic plaque in vivo. Moreover, GSK-3β inhibition by UTMD did not influence the viability of the foam cells. Collectively, our results indicate that GSK-3β could be a potential target for anti-atherogenic interventions and, in particular, can improve the stability of AS plaques in combination with UTMD.

Keywords: Glycogen synthase kinase 3β; THP-1 macrophage-derived foam cells; Ultrasound-targeted microbubble destruction; atherosclerotic plaque stability.