scholarly journals Drug repurposing and therapeutic anti-microRNA predictions for inhibition of oxidized low-density lipoprotein-induced vascular smooth muscle cell-associated diseases

2017 ◽  
Vol 15 (01) ◽  
pp. 1650043 ◽  
Author(s):  
Shun-Tsung Chen ◽  
Chien-Hung Huang ◽  
Victor C. Kok ◽  
Chi-Ying F. Huang ◽  
Jin-Shuei Ciou ◽  
...  

Drug repurposing is a new method for disease treatments, which accelerates the identification of new uses for existing drugs with minimal side effects for patients. MicroRNA-based therapeutics are a class of drugs that have been used in gene therapy following the FDA’s approval of the first anti-sense therapy. This study examines the effects of oxLDL on vascular smooth muscle cells (VSMCs) and identifies potential drugs and antimiRs for treating VSMC-associated diseases. The Connectivity Map (cMap) database is utilized to identify potential new uses of existing drugs. The success of the identifications was supported by MTT assay, clonogenic assay and clinical trial data. Specifically, 37 drugs, some of which are undergoing clinical trials, were identified. Three of the identified drugs exhibit IC50 activities. Among the 37 drugs’ targets, three differentially expressed genes (DEGs) are identified as drug targets by using both the DrugBank and the NCBI PubChem Compound databases. Also, one DEG, DNMT1, which is regulated by 17 miRNAs, where these miRNAs are potential targets for developing antimiR-based miRNA therapy, is found.

Author(s):  
Jiefang Chen ◽  
Shulan Pi ◽  
Cheng Yu ◽  
Hanqing Shi ◽  
Yuxiao Liu ◽  
...  

Objective: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1 + α-SMA + (α-smooth muscle actin), P2Y12 + , or P2Y12 + LRP1 + cells in plaques from apoE −/− mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1 + α-SMA + cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE −/− mice fed a high-fat diet. Conclusions: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.


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