Metformin Alters the MicroRNA Profile of High Glucose-Induced Human Umbilical Vein Endothelial Cells
Metformin Alters miRNAs in Hyperglycemic HUVECs
Abstract
MicroRNAs (miRNAs) contribute to the progression of vascular complications in diabetes. Metformin has been shown to protect against endothelial dysfunction in diabetes; however, it remained unclear whether this effect was mediated through the modulation of miRNAs. To gain insight into the effects of metformin on miRNA profile in endothelial cells treated with high glucose, we utilised next gene sequencing (NGS) and further conducted the bioinformatic analyses to explore the associated target genes and pathways. NGS revealed 19 miRNAs with differential expression, including nine downregulated and 10 upregulated miRNAs. Gene ontology highlighted molecular functions and biological processes such as ErbB-2 class receptor binding and receptor activity regulation, which are crucial in mediating the involvement of metformin in diabetes-induced oxidative stress and apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway analysis connected these miRNAs to diabetes-related pathways, such as type II diabetes mellitus and phosphatidylinositol signaling system. Furthermore, network analysis of protein interaction identified important genes, such as glyceraldehyde-3-phosphate dehydrogenase, sirtuin 1 and Jun proto-oncogene as hub genes in modulating oxidative stress and apoptosis. In conclusion, this study elucidates how metformin exerts its protective effects on diabetic vascular endothelial dysfunction by modulating miRNAs. These findings could help develop more targeted therapeutic interventions for diabetes.
Keywords :
Diabetes; high glucose; human umbilical vein endothelial cells; metformin; microRNA,
Abstrak
MikroRNA (miRNA) menyumbang kepada perkembangan komplikasi vaskular akibat diabetes. Metformin telah terbukti dapat melindungi daripada disfungsi endotelium dalam kalangan pesakit diabetes; namun, ia masih belum jelas sama ada kesan ini diperantarai melalui modulasi miRNA. Untuk memahami kesan metformin terhadap profil miRNA dalam sel endotelium yang dirawat dengan glukosa tinggi, kami telah menggunakan penjujukan generasi hadapan (NGS) dan seterusnya menjalankan analisis bioinformatik untuk meneroka gen sasaran serta laluan yang terlibat. Hasil NGS mengenal pasti sebanyak 19 miRNA yang diekspresi secara berbeza, termasuk sembilan miRNA berekspresi rendah dan 10 miRNA berekspresi tinggi. Analisis ontologi gen menunjukkan fungsi molekul dan proses biologi seperti pengikatan reseptor kelas ErbB-2 dan pengawalaturan aktiviti reseptor yang penting dalam memperantara penglibatan metformin terhadap tekanan oksidatif dan apoptosis yang disebabkan oleh diabetes. Analisis tapak jalan Kyoto Encyclopedia of Genes and Genomes (KEGG) pula menghubungkan miRNA dengan tapak jalan berkaitan diabetes, seperti diabetes mellitus jenis II dan sistem isyarat fosfatidilinositol. Tambahan lagi, analisis rangkaian interaksi protein mengenalpasti beberapa gen utama, seperti dehidrogenase gliseraldehid-3-fosfat, sirtuin 1, dan Jun proto-onkogen sebagai gen hub dalam memperantarai tekanan oksidatif dan apoptosis. Kesimpulannya, kajian ini menunjukkan metformin memberi kesan perlindungan terhadap disfungsi endotelium vaskular diabetes melalui modulasi miRNA. Penemuan ini boleh membantu untuk membangunkan intervensi terapeutik yang lebih bersasar bagi penyakit diabetes.
Kata Kunci :
Diabetes; glukosa tinggi; metformin; mikroRNA; sel endotelium vena umbilikus manusia,
Correspondance Address
Azizah Ugusman. Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: +603-91458614 Email: dr.azizah@hctm.ukm.edu.my
