Presentation_1_Atorvastatin Inhibits Inflammatory Response, Attenuates Lipid Deposition, and Improves the Stability of Vulnerable Atherosclerotic Plaques by Modulating Autophagy.PDF

<p>Atherosclerosis is a chronic disease comprising intima malfunction and arterial inflammation. Recent studies have demonstrated that autophagy could inhibit inflammatory response in atherosclerosis and exert subsequent atheroprotective effects. Our previous study also demonstrated the role of autophagy in the inhibition of inflammation by atorvastatin in vitro. Therefore, in the present study, we aimed to determine whether atorvastatin could upregulate autophagy to inhibit inflammatory cytokines secretion, lipid accumulation, and improve vulnerable plaque stability, both in vitro and in vivo. First, we established a vulnerable atherosclerotic plaque mouse model through partial ligation of left common carotid artery and left renal artery to explore the effect of atorvastatin on vulnerable plaques. The results showed that atorvastatin could enhance the stability of vulnerable atherosclerotic plaques and reduce the lesion area in the aorta. Atorvastatin could also inhibit NLRP3 inflammasome activation and inflammatory cytokines, such as IL-1β, TNF-α, and IL-18 secretion in vivo. Atorvastatin treatment upregulated the expression of autophagy-related protein microtubule-associated protein light chain (LC3B) and downregulated the expression of SQSTM1/p62, which suggested that autophagy was activated in vulnerable plaques. Transmission electron microscopy further demonstrated the atorvastatin-induced increase in autophagy activity in vulnerable atherosclerotic plaques. We employed oxidized low-density lipoprotein (ox-LDL) to stimulate RAW264.7 cells with atorvastatin, which showed that atorvastatin could attenuate lipid deposition, ameliorate inflammation, inhibit NLRP3 inflammasome activation, and enhance autophagy in vitro. All these beneficial effects were abolished by 3-methyladenine treatment, an autophagy inhibitor. Atorvastatin also significantly inhibited the phosphorylation of mTOR, which strongly suggested the involvement of the mTOR pathway. Our study proposed a new role for atorvastatin as an autophagy inducer to exert anti-inflammatory and atheroprotective effects, to stabilize vulnerable atherosclerotic plaques.</p

Detection of ADAMTS‑4 Activity Using a Fluorogenic Peptide-Conjugated Au Nanoparticle Probe in Human Knee Synovial Fluid

A disintegrin and metalloproteinase with thrombospondin motif-4 (ADAMTS-4) plays a pivotal role in degrading aggrecan, which is an early event in cartilage degrading joint diseases such as osteoarthritis (OA). Detection of ADAMTS-4 activity could provide useful clinical information for early diagnosis of such diseases and disease-modifying therapy. Therefore, we developed a ADAMTS-4 detective fluorescent turn-on AuNP probe (ADAMTS-4-D-Au probe) by conjugating gold nanoparticles with a FITC-modified ADAMTS-4-specific peptide (DVQEFRGVTAVIR). When the ADAMTS-4-D-Au probe was incubated with ADAMTS-4, the fluorescence recovered and fluorescence intensity markedly increased in proportion to concentrations of ADAMTS-4 and the probe. A nearly 3-fold increase in fluorescent intensity in response to only 3.9 pM of ADAMTS-4 was detected, whereas almost no fluorescence recovery was observed when the probe was incubated with matrix metalloproteinase (MMP)-1, -3, and -13. These results indicate a relative high sensitivity and specificity of the probe. Moreover, ADAMTS-4-D-Au probe was used to detect ADAMTS-4 activity in synovial fluid from 11 knee surgery patients. A substantial increase in fluorescent intensity was observed in the acute joint injury group as compared to the chronic joint injury and end-stage OA groups, indicating that this simple and low-cost sensing system might serve as a new detection method for ADAMTS-4 activity in biological samples and in screens for inhibitors for ADAMTS-4-related joint diseases. Additionally, this probe could be a potential biomarker for early diagnosis of cartilage-degrading joint diseases