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

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          Abstract

          Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease, which is common but rarely diagnosed. Noninvasive biomarkers are urgently required to assist in the diagnosis of CLI. Accumulating evidence indicates that miRNAs play an important role in the development of various diseases. In this study, microarray profiling revealed 11 miRNAs with significantly altered expression in four T2DM patients with CLI compared with that in four sex- and age-matched T2DM patients without CLI. In independent cohorts, qRT-PCR validation confirmed the increased miRNA-4739 level in patients with CLI versus patients without CLI. miRNA-4739 levels increased with FPG and HbA1c (all P < 0.05). After adjusting for the risk factors, miRNA-4739 levels were found to be associated with an increased odds ratio (OR) of T2DM with CLI (OR =12.818, 95% confidence intervals (CI) 1.148 to 143.143, P = 0.038). ROC curve analysis revealed that the area under the curve (AUC) of miR-4739+confounding risk factors was 0.94 (95% CI 0.891 to 0.998, P < 0.001), which was higher than that of confounding risk factors (AUC 0.94 vs. 0.91, 95% CI -0.122 to 0.060, P > 0.05) and of miR-4739 (AUC 0.94 vs. 0.69, 95% CI -0.399 to -0.101, P < 0.001), respectively. We conclude that elevated plasma miRNA-4739 levels are independently associated with CLI in T2DM patients. miRNA-4739 is implicated as a novel diagnostic marker and a potential therapeutic target for CLI in diabetes.

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          Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia.

          Andrea Caporali, Marco Meloni, Christine Völlenkle … (2011)
          Diabetes mellitus impairs endothelial cell (EC) function and postischemic reparative neovascularization by molecular mechanisms that are not fully understood. microRNAs negatively regulate the expression of target genes mainly by interaction in their 3' untranslated region. We found that microRNA-503 (miR-503) expression in ECs is upregulated in culture conditions mimicking diabetes mellitus (high D-glucose) and ischemia-associated starvation (low growth factors). Under normal culture conditions, lentivirus-mediated miR-503-forced expression inhibited EC proliferation, migration, and network formation on Matrigel (comparisons versus lentivirus.GFP control). Conversely, blocking miR-503 activity by either adenovirus-mediated transfer of a miR-503 decoy (Ad.decoymiR-503) or by antimiR-503 (antisense oligonucleotide) improved the functional capacities of ECs cultured under high D-glucose/low growth factors. We identified CCNE1 and cdc25A as direct miR-503 targets which are downregulated by high glucose/low growth factors in ECs. Next, we obtained evidence that miR-503 expression is increased in ischemic limb muscles of streptozotocin-diabetic mice and in ECs enriched from these muscles. Moreover, Ad.decoymiR-503 delivery to the ischemic adductor of diabetic mice corrected diabetes mellitus-induced impairment of postischemic angiogenesis and blood flow recovery. We finally investigated miR-503 and target gene expression in muscular specimens from the amputated ischemic legs of diabetic patients. As controls, calf biopsies of nondiabetic and nonischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and it inversely correlated with cdc25 protein expression. Plasma miR-503 levels were also elevated in the diabetic individuals. Our data suggest miR-503 as a possible therapeutic target in diabetic patients with critical limb ischemia.
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            Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms.

            Luigi Ferrucci, J M Guralnik, Christopher Pearce … (2004)
            Among individuals with lower-extremity peripheral arterial disease (PAD), specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally related to the degree of functional impairment. However, relations between these clinical characteristics and objectively measured functional decline are unknown. To define whether PAD, ABI, and specific leg symptoms predict functional decline at 2-year follow-up. Prospective cohort study among 676 consecutively identified individuals (aged > or =55 years) with and without PAD (n = 417 and n = 259, respectively), with baseline functional assessments occurring between October 1, 1998, and January 31, 2000, and follow-up assessments scheduled 1 and 2 years thereafter. PAD was defined as ABI less than 0.90, and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups. Mean annual changes in 6-minute walk performance and in usual-paced and fast-paced 4-m walking velocity, adjusted for age, sex, race, prior-year functioning, comorbid diseases, body mass index, pack-years of cigarette smoking, and patterns of missing data. Lower baseline ABI values were associated with greater mean (95% confidence interval) annual decline in 6-minute walk performance (-73.0 [-142 to -4.2] ft for ABI <0.50 vs -58.8 [-83.5 to -34.0] ft for ABI 0.50 to <0.90 vs -12.6 [-40.3 to 15.1] ft for ABI 0.90-1.50, P =.02). Compared with participants without PAD, PAD participants with leg pain on exertion and rest at baseline had greater mean annual decline in 6-minute walk performance (-111 [-173 to -50.0] ft vs -8.67 [-36.9 to 19.5] ft, P =.004), usual-pace 4-meter walking velocity (-0.06 [-0.09 to -0.02] m/sec vs -0.01 (-0.03 to 0.003] m/sec, P =.02), and fastest-pace 4-meter walking velocity (-0.07 [-0.11 to -0.03] m/sec vs -0.02 [-0.04 to -0.006] m/sec, P =.046). Compared with participants without PAD, asymptomatic PAD was associated with greater mean annual decline in 6-minute walk performance (-76.8 (-135 to -18.6] ft vs -8.67 (-36.9 to 19.5] ft, P =.04) and an increased odds ratio for becoming unable to walk for 6 minutes continuously (3.63; 95% confidence interval, 1.58-8.36; P =.002). Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up. Previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance to than lack of disease progression.
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              Therapeutic angiogenesis for critical limb ischaemia.

              Brian Annex (2013)
              Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. The lower extremity is the most-common location for PAD. Critical limb ischaemia (CLI) is the most-severe clinical manifestation of PAD. Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in CLI is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with CLI are unsuitable for revascularization, or the procedure is unsuccessful. Angiogenesis is the growth and proliferation of blood vessels from an existing vascular structure. In therapeutic angiogenesis, attempts are made to utilize blood vessel growth to augment perfusion. In this Review, data from phase II and III clinical trials of therapeutic angiogenesis in patients with PAD will be presented and discussed. Potential explanations for the limited success of therapeutic angiogenesis in humans will be viewed in the context of advances in our understanding of the complex mechanisms underlying angiogenesis and vascular remodelling. This Review will also cover how advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion.
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                Author and article information

                Contributors
                Jue Liu:
                ORCID: http://orcid.org/0000-0002-0338-2257
                Ai-ping Deng:
                ORCID: http://orcid.org/0000-0003-2119-7570
                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date Collection: 2018
                Publication date (Electronic): 14 November 2018
                Volume: 2018
                Electronic Location Identifier: 4232794
                Affiliations
                1Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430021, Hubei, China
                2Department of Pain, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430021, Hubei, China
                3Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430021, Hubei, China
                Author notes

                Academic Editor: Konstantinos Kantartzis

                Author information
                http://orcid.org/0000-0003-4280-3461
                http://orcid.org/0000-0002-0338-2257
                http://orcid.org/0000-0003-2119-7570
                Article
                DOI: 10.1155/2018/4232794
                PMC ID: 6261237
                SO-VID: 1f0da8be-7d63-4488-8caa-0466762052a6
                Copyright © Copyright © 2018 Ju-yi Li et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 1 September 2018
                Date revision received : 19 October 2018
                Date accepted : 31 October 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81603013
                Award ID: 81800704
                Funded by: Health and Family Planning Commission of Hubei Province
                Award ID: WJ2017M183
                Funded by: Health and Family Planning Commission of Wuhan
                Award ID: WX18M02
                Funded by: Research of Wuhan Science and Technology Bureau
                Award ID: 2017060201010204
                Categories
                Subject: Research Article

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