cardiovascular-agents and tanespimycin

Emerging evidences indicate that heat-shock protein 90 (HSP90) is associated with atherogenesis. However, the effect of HSP90 on plaque stability is largely unknown. In this study, we explored the role of HSP90 in plaque development and its regulatory mechanisms on vasculature.. Heat-shock protein90-overexpression lentivirus (Lenti-HSP90) was used to transfect apoE. As a result, HSP90 gene overexpression led to reduction in en face plaque area and increase in unstable plaque with heavier accumulation of lipids. Concomitantly, more macrophages, less smooth muscle cells, and collagen were generated, suggesting aggravated inflammation. However, inhibition of HSP90 with 17-AAG, a HSP90-inhibitor, induced opposing effects. Moreover, HSP90 upregulated plaque MMP-8, which might be the underlying mechanism of the change in plaque vulnerability index. Further, the translocation of NF-κB was promoted by HSP90, while inhibition of NF-κB significantly reduced MMP-8 production, which is upregulated by HSP90.. These findings suggested that HSP90 governs plaque development and vulnerability, as well as inflammation, at least in part via MMP-8 and NF-κB signaling pathways.

Topics: Animals; Apolipoproteins E; Benzoquinones; Cardiovascular Agents; Carotid Arteries; Carotid Artery Diseases; Disease Models, Animal; Gene Expression Regulation; Genetic Vectors; HSP90 Heat-Shock Proteins; Inflammation; Inflammation Mediators; Lactams, Macrocyclic; Lentivirus; Male; Matrix Metalloproteinase 8; Mice; Mice, Knockout; NF-kappa B; Plaque, Atherosclerotic; RAW 264.7 Cells; Signal Transduction; Transduction, Genetic; Transfection