Abstract
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease. It is characterized by chronic pain at rest, skin ulcerations, and gangrene tissue loss. CLI is a highly morbid condition, resulting in a severely diminished quality of life and a significant risk of mortality. The primary goal of therapy for CLI is to restore blood flow to the affected limb, which is only possible by surgery, but is inadvisable in up to 50% of patients. This subset of patients who are not candidates for revascularisation are referred to as “no-option” patients and are the focus of investigation for novel therapeutic strategies. Angiogenesis, arteriogenesis and vasculogenesis are the processes whereby new blood vessel networks form from the pre-existing vasculature and primordial cells, respectively. In therapeutic angiogenesis, exogenous stimulants are administered to promote angiogenesis and augment limb perfusion, offering a potential treatment option for “no option” patients. However, to date, very few clinical trials of therapeutic angiogenesis in patients with CLI have reported clinically significant results, and it remains a major challenge. Ghrelin, a 28-amino acid peptide, is emerging as a potential novel therapeutic for CLI. In pre-clinical models, exogenous ghrelin has been shown to induce therapeutic angiogenesis, promote muscle regeneration, and reduce oxidative stress via the modulation of microRNAs (miRs). miRs are endogenous, small, non-coding ribonucleic acids of ~20–22 nucleotides which regulate gene expression at the post-transcriptional level by either translational inhibition or by messenger ribonucleic acid cleavage. This review focuses on the mounting evidence for the use of ghrelin as a novel therapeutic for CLI, and highlights the miRs which orchestrate these physiological events.
Highlights
Peripheral artery disease (PAD) is characterized by the narrowing or occlusion of systemic arteries impeding blood supply to the extremities [1]
This review presents the concepts of therapeutic angiogenesis and highlights the limitations associated with advancing current treatments for Critical limb ischemia (CLI)
In Russia, a plasmid DNA gene product encoding vascular endothelial growth factor (VEGF) 165 “Neovasculgen” [40] is approved for clinical use in the treatment of PAD. While this agent is approved in Russia, a recent meta-analysis of randomized control trials shows no consistent benefit of any gene therapy for promoting therapeutic angiogenesis in PAD [20]
Summary
Peripheral artery disease (PAD) is characterized by the narrowing or occlusion of systemic arteries impeding blood supply to the extremities [1]. Therapeutic angiogenesis is emerging as a potential treatment approach for “no-option” CLI patients by stimulating neovascularization, improving limb perfusion, and aiding tissue regeneration [17]. Angiogenic agents, such as gene or cell therapy, have been the focus of investigation, with the aim of inducing a pro-angiogenic milieu in the affected ischemic limb. The results from clinical trials using such agents have shown little clinical benefit regarding primary outcome measures (i.e., patency, amputation-free survival, major limb adverse effects) [18,19,20] This highlights both the complexity of therapeutic angiogenesis and the need to develop new agents for the management of CLI. The emergence of ghrelin as a novel therapeutic for CLI is explored and the molecular mechanisms that underpin ghrelin’s beneficial actions highlighted
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