MicroRNAs in peripheral artery disease: potential biomarkers and pathophysiological mechanisms

Abstract

Peripheral artery disease (PAD) is a disease of atherosclerosis in the lower extremities. PAD carries a massive burden worldwide, while diagnosis and treatment options are often lacking. One of the key points of research in recent years is the involvement of microRNAs (miRNAs), which are short 20-25 nucleotide single-stranded RNAs that can act as negative regulators of post-transcriptional gene expression. Many of these miRNAs have been discovered to be misregulated in PAD patients, suggesting a potential utility as biomarkers for PAD diagnosis. miRNAs have also been shown to play an important role in many different pathophysiological aspects involved in the initiation and progression of the disease including angiogenesis, hypoxia, inflammation, as well as other cellular functions like cell proliferation and migration. The research on miRNAs in PAD has the potential to lead to a whole new class of diagnostic tools and treatments.

Keywords: angiogenesis; biomarkers; critical limb ischemia; hypoxia; intermittent claudication; non-coding RNAs.

Figure 1.

Summary of microRNA biogenesis. This figure summarizes the processing of miRNAs from transcription to a mature miRNA-RISC. First the pri-miRNA is transcribed and forms into a hairpin structure. RNAse III Drosha then cleaves the excess base pairs, forming a ~70 base pair stem-loop structure. Following cleavage, the GTP-dependent Exportin 5 transporter exports the pre-miRNA from the nucleus. Outside the nucleus, RNase III Dicer further cleaves the loop structure, separating the 2 strands of RNA, which leaves a 20-25 nucleotide single-stranded mature miRNA. Argonaute and other binding proteins are incorporated, forming the final RNA-inducing silencing complexes (RISC).

Figure 2.

Summary of microRNA action. This figure summarizes the mechanisms of action of miRNA-RISC acting on mRNAs to downregulate their expression. The complex bind to the 5′ UTR of mRNAs and either cleaves them or reduces their translational efficiency or stability. RISC, RNA-inducing silencing complexes.

Figure 3.

Summary of microRNAs in PAD. This figure summarizes the different miRNAs that have been suggested as biomarkers for PAD. In addition, other miRNAs presented have been found to play a role in different aspects of PAD pathophysiology including angiogenesis, hypoxia/reactive oxygen species, inflammation, mitochondrial function, or other cell functions.