Ghrelin, MicroRNAs, and Critical Limb Ischemia: Hungering for a Novel Treatment Option

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.

Circulating MicroRNA-4739 May Be a Potential Biomarker of Critical Limb Ischemia in Patients with Diabetes

“…Type 2 diabetes mellitus (T2DM) is associated with accelerated peripheral arterial disease (PAD), which is characterized by the narrowing or occlusion of systemic arteries. This condition impeded blood supply to the extremities and is associated with significant cardiovascular morbidity and mortality [ 1 , 2 ]. Critical limb ischemia (CLI) is the most severe manifestation of PAD and seriously decreases blood flow to the extremities, which increases the risk of foot ulcers, amputation, and vascular death, especially in diabetic patients [ 3 ].…”

“…The increasing number of people being diagnosed with diabetes mellitus, and the global escalation in the aging population, is expected to exacerbate the CLI burden [ 2 ]. T2DM is a major contributor to CLI and although the biological mechanisms remain to be fully elucidated, it is generally believed that contributing factors include oxidative and glycemic stress, chronic low grade inflammation, and impaired vascular tissue repair [ 4 – 6 ].…”

“…Currently, the prognosis of patients with CLI is very poor. Only 10% to 30% of patients with PAD have the classic clinical symptoms [ 9 ]; however, patients with a confirmed diagnosis of CLI have a 25% to 40% chance of lower limb amputation and approximately a 20% chance of mortality, with severely diminished quality of life [ 2 , 10 ].…”

Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease

“…Acylated ghrelin and its receptor (GHS-R) are ubiquitous throughout the cardiovascular system 29,30 , suggesting ghrelin has a prominent role in cardiovascular homeostasis 31 . To date, a growing body of literature advocates the beneficial effects of AG in maintaining cardiovascular health 6,32,33 .…”

On the Cutting Edge: Wound Care for the Endovascular Specialist

“…While the precise, controlled effects of mIRs have yet to be elucidated, ghrelin, a hormone with pleiotropic effects throughout the body, has demonstrated promise in the upregulation of miRs beneficial in CLI. 139 Currently, the widespread use of tissue growth factors and miR therapy in CLI wound healing is prohibited by their cost and lack of universal approval. Perhaps with the support of larger trials currently underway, this may change in the near future.…”