Dinesh Kumar1, Rajiv Narang2, Daman Saluja1,3, Kamna Srivastava4. 1. Dr. B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007, India. 2. Department of Cardiology, All India Institute of Medical Sciences, New Delhi, 110029, India. 3. Delhi School of Public Health, IoE, University of Delhi, New Delhi, India. 4. Dr. B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007, India. Kamna605@gmail.com.
Abstract
BACKGROUND: Atherosclerosis, a progressive manifestation of coronary artery disease, has been observed to be regulated by microRNAs (miRNAs) targeting various protein-coding genes involved in several pathophysiological events of coronary artery disease. OBJECTIVE: In our previous report, we identified differential expression profiles of candidate miRNAs, miR-133b and miR-21, in patients with coronary artery disease as compared with controls, suggesting their possible implication in the pathophysiology of coronary artery disease. To better understand the functional role of these miRNAs, we sought to predict and validate their target genes while assessing the expression pattern of these genes in patients with coronary artery disease, as well as in macrophages. METHODS: Potential target genes of miR-133b and miR-21 were predicted bioinformatically followed by validation through the identification of their expression at the protein level in patients with coronary artery disease (n-30), as well as in macrophages treated with respective miRNA inhibitors (antagomiRs), through immunoblotting. RESULTS: SGPP1, a gene associated with the sphingolipid pathway, was predicted to be a potential target gene of miR-133b while ATG5 and LRP6 were target genes of miR-21 while being associated with autophagy and Wnt signalling pathways, respectively. SGPP1 was observed to be upregulated significantly (p = 0.019) by 2.07-fold, whereas ATG5 and LRP6 were found to be downregulated (p = 0.026 and 0.007, respectively) by 3.28-fold and 8.46-fold, respectively, in patients with coronary artery disease as compared with controls. Expression patterns of all the genes were also found to be modulated when cells were treated with respective miRNA inhibitors. CONCLUSIONS: Results from the present study suggest that SGPP1, ATG5 and LRP6, target genes of miR-133b and miR-21, may serve as potential therapeutic hotspots in the management of coronary artery disease, which undoubtedly merit further experimental confirmation.
BACKGROUND: Atherosclerosis, a progressive manifestation of coronary artery disease, has been observed to be regulated by microRNAs (miRNAs) targeting various protein-coding genes involved in several pathophysiological events of coronary artery disease. OBJECTIVE: In our previous report, we identified differential expression profiles of candidate miRNAs, miR-133b and miR-21, in patients with coronary artery disease as compared with controls, suggesting their possible implication in the pathophysiology of coronary artery disease. To better understand the functional role of these miRNAs, we sought to predict and validate their target genes while assessing the expression pattern of these genes in patients with coronary artery disease, as well as in macrophages. METHODS: Potential target genes of miR-133b and miR-21 were predicted bioinformatically followed by validation through the identification of their expression at the protein level in patients with coronary artery disease (n-30), as well as in macrophages treated with respective miRNA inhibitors (antagomiRs), through immunoblotting. RESULTS: SGPP1, a gene associated with the sphingolipid pathway, was predicted to be a potential target gene of miR-133b while ATG5 and LRP6 were target genes of miR-21 while being associated with autophagy and Wnt signalling pathways, respectively. SGPP1 was observed to be upregulated significantly (p = 0.019) by 2.07-fold, whereas ATG5 and LRP6 were found to be downregulated (p = 0.026 and 0.007, respectively) by 3.28-fold and 8.46-fold, respectively, in patients with coronary artery disease as compared with controls. Expression patterns of all the genes were also found to be modulated when cells were treated with respective miRNA inhibitors. CONCLUSIONS: Results from the present study suggest that SGPP1, ATG5 and LRP6, target genes of miR-133b and miR-21, may serve as potential therapeutic hotspots in the management of coronary artery disease, which undoubtedly merit further experimental confirmation.
Authors: Yury I Miller; Mi-Kyung Chang; Christoph J Binder; Peter X Shaw; Joseph L Witztum Journal: Curr Opin Lipidol Date: 2003-10 Impact factor: 4.776
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