Mechanisms of action of metformin and its regulatory effect on microRNAs related to angiogenesis

Angiogenesis is rapidly initiated in response to pathological conditions and is a key target for pharmaceutical intervention in various malignancies. Anti-angiogenic therapy has emerged as a potential and effective therapeutic strategy for treating cancer and cardiovascular-related diseases. Metformin, a first-line oral antidiabetic agent for type 2 diabetes mellitus (T2DM), not only reduces blood glucose levels and improves insulin sensitivity and exerts cardioprotective effects but also shows benefits against cancers, cardiovascular diseases, and other diverse diseases and regulates angiogenesis. MicroRNAs (miRNAs) are endogenous noncoding RNA molecules with a length of approximately 19-25 bases that are widely involved in controlling various human biological processes. A large number of miRNAs are involved in the regulation of cardiovascular cell function and angiogenesis, of which miR-21 not only regulates vascular cell proliferation, migration and apoptosis but also plays an important role in angiogenesis. The relationship between metformin and abnormal miRNA expression has gradually been revealed in the context of numerous diseases and has received increasing attention. This paper reviews the drug-target interactions and drug repositioning events of metformin that influences vascular cells and has benefits on angiogenesis-mediated effects. Furthermore, we use miR-21 as an example to explain the specific molecular mechanism underlying metformin-mediated regulation of the miRNA signaling pathway controlling angiogenesis and vascular protective effects. These findings may provide a new therapeutic target and theoretical basis for the clinical prevention and treatment of cardiovascular diseases.