MicroRNA-93 Controls Perfusion Recovery After Hindlimb Ischemia by Modulating Expression of Multiple Genes in the Cell Cycle Pathway

Hazarika, Surovi; Farber, Charles R.; Dokun, Ayotunde O.; Pitsillides, Achillieas N.; Wang, Tao; Lye, R. John; Annex, Brian H.

doi:10.1161/circulationaha.112.000860

Cited by 91 publications

(131 citation statements)

References 34 publications

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“…In the initial RTP, we included 127 genes that are known to be involved in neovascularization from both literature and our own studies (Online Table IA). As anticipated, we observed enrichment of putative binding sites for several microRNAs that were previously reported to influence postischemic neovascularization, including miR-17/92a 9 (29 and 21 putative target genes, respectively), miR-106b/93/25 8,14 (29,29, and 21 putative target genes, respectively), the miR-15a family 10,11,25 (26 putative target genes), miR-503 13 (11 putative target genes), and miR-100 7 (2 putative target genes) but not, for example, miR-126. 6 However, more outspoken was the enrichment of putative binding sites for 27 microRNAs from the 14q32 microRNA gene cluster, including miR-329, miR-494, and miR-495 (20, 31, and 44 putative target genes, respectively).…”

Section: Reverse Target Predictionsupporting

confidence: 85%

“…All findings of RTP1 are given in Online Tables IB and IC. In the second RTP, we included 70 additional genes that we found upregulated in the early stages of vascular remodeling in murine tissue after HLI induced by single ligation of the femoral artery, a model for effective neovascularization (Online Table IIA). We again observed enrichment of binding sites for miR-17/92 (8 and 4 putative target genes, respectively), miR-106/93/25 (8,8, and 4 putative target genes, respectively), the miR-15a family (3 putative target genes), miR-503 (5 putative target genes), and miR-100 (1 putative target genes). Furthermore, enrichment of binding sites for 26 of the initial 27 identified 14q32 microRNAs was recovered, including miR-329, miR-494, and miR-495 (10, 8, and 7 putative target genes, respectively).…”

Section: Reverse Target Predictionmentioning

confidence: 62%

“…[6][7][8][9][10][11][12][13][14] In the present study, we exploited the master switch character of microRNAs to identify microRNAs that play a regulatory role in neovascularization as a whole, including both angiogenesis and arteriogenesis. We performed a reverse target prediction (RTP) analysis on a set of ≈200 genes involved in all facets of angiogenesis and arteriogenesis, aiming to identify microRNAs that can target multiple neovascularization genes.…”

Section: Welten Et Al 14q32 Micrornas In Neovascularization 697mentioning

confidence: 99%

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Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia

Welten

Bastiaansen

Jong

et al. 2014

Circulation Research

132

161

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Rationale: Effective neovascularization is crucial for recovery after cardiovascular events. Objective: Because microRNAs regulate expression of up to several hundred target genes, we set out to identify microRNAs that target genes in all pathways of the multifactorial neovascularization process. Using www.targetscan. org, we performed a reverse target prediction analysis on a set of 197 genes involved in neovascularization. We found enrichment of binding sites for 27 microRNAs in a single microRNA gene cluster. Microarray analyses showed upregulation of 14q32 microRNAs during neovascularization in mice after single femoral artery ligation. Methods and Results:Gene silencing oligonucleotides (GSOs) were used to inhibit 4 14q32 microRNAs, miR-329, miR-487b, miR-494, and miR-495, 1 day before double femoral artery ligation. Blood flow recovery was followed by laser Doppler perfusion imaging. All 4 GSOs clearly improved blood flow recovery after ischemia. Mice treated with GSO-495 or GSO-329 showed increased perfusion already after 3 days (30% perfusion versus 15% in control), and those treated with GSO-329 showed a full recovery of perfusion after 7 days (versus 60% in control). Increased collateral artery diameters (arteriogenesis) were observed in adductor muscles of GSO-treated mice, as well as increased capillary densities (angiogenesis) in the ischemic soleus muscle. In vitro, treatment with GSOs led to increased sprout formation and increased arterial endothelial cell proliferation, as well as to increased arterial myofibroblast proliferation. Conclusions Welten et al 14q32 MicroRNAs in Neovascularization 697Both arteriogenesis and angiogenesis are highly multifactorial processes, and yet clinical trials aiming to induce neovascularization in patients with occlusive arterial disease have so far only focused on single-factor therapeutics, such as growth factors (eg, vascular endothelial growth factor A [VEGFA] and basic fibroblast growth factor [bFGF]). Unfortunately, these trials were less successful than anticipated.1,3,4 Growth factors only target 1 of multiple processes required for efficient neovascularization. Therefore, there is a need for novel proarteriogenic and proangiogenic factors that can act as master switches in neovascularization.MicroRNAs are endogenous RNA molecules that downregulate expression of their target genes.5 MicroRNAs do not completely silence their target genes, but rather downtune their expression. However, because each microRNA has multiple, up to several hundred, target genes, changes in microR-NA expression can have a major impact. Inhibition of a single microRNA can thus lead to activation of entire multifactorial physiological processes.Several studies have been published on the effects of microRNA inhibition on neovascularization, but in general, the focus of these studies lies with angiogenesis alone, not arteriogenesis. [6][7][8][9][10][11][12][13][14] In the present study, we exploited the master switch character of microRNAs to identify microRNAs that play a regulat...

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Section: Reverse Target Predictionsupporting

confidence: 85%

Section: Reverse Target Predictionmentioning

confidence: 62%

Section: Welten Et Al 14q32 Micrornas In Neovascularization 697mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia

Welten

Bastiaansen

Jong

et al. 2014

Circulation Research

132

161

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“…Based on the studies regarding hind‐limb ischaemia and tumours, miR‐93 promotes angiogenesis and/or inhibits angiogenesis in various molecular pathways 124. Many studies support the roles of miR‐93 in promoting angiogenesis and improving EC proliferation, migration, spreading and tube formation 124, 125.…”

Section: Mirnas Regulated By Pro‐or Anti‐angiogenesis Factors or Hypomentioning

confidence: 99%

The regulatory role of microRNAs in angiogenesis‐related diseases

Sun

Lei

et al. 2018

J Cellular Molecular Medi

116

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MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression at a post‐transcriptional level via either the degradation or translational repression of a target mRNA. They play an irreplaceable role in angiogenesis by regulating the proliferation, differentiation, apoptosis, migration and tube formation of angiogenesis‐related cells, which are indispensable for multitudinous physiological and pathological processes, especially for the occurrence and development of vascular diseases. Imbalance between the regulation of miRNAs and angiogenesis may cause many diseases such as cancer, cardiovascular disease, aneurysm, Kawasaki disease, aortic dissection, phlebothrombosis and diabetic microvascular complication. Therefore, it is important to explore the essential role of miRNAs in angiogenesis, which might help to uncover new and effective therapeutic strategies for vascular diseases. This review focuses on the interactions between miRNAs and angiogenesis, and miRNA‐based biomarkers in the diagnosis, treatment and prognosis of angiogenesis‐related diseases, providing an update on the understanding of the clinical value of miRNAs in targeting angiogenesis.

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“…70 MicroRNA93 shows lower expression in animals genetically predisposed to severe clinical phenotypes such as hindlimb ischemia. 71 In animal models, there is abundant evidence that therapies stimulating angiogenesis increase skeletal muscle perfusion and restore functional status.…”

Section: Systemic and Local Inflammationmentioning

confidence: 99%

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

Hamburg

Creager

2017

Circ J

154

124

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estimates a more than 30% increase in deaths and disability attributable to PAD between 2005 and 2015, which is largely determined by population aging. 3,12 PAD prevalence escalates with advancing age, affecting 1 in 10 adults older than 70 years. In addition to age, smoking and diabetes are the strongest risk factors for PAD across the world. A comprehensive global evaluation of PAD found that its prevalence and risk factors are similar in high-income countries to low-and middle-income countries. 2,13 Lower socioeconomic status is a newly recognized risk factor for PAD. 14 Importantly, there has been a greater increase in PAD prevalence in low-and middle-income countries, rising by 28.7% from 2000 to 2010 as compared with 13.1% in high-income countries. 2, 15 The changing burden of PAD is also greater in women as compared with men.The health implications of PAD derive from both its limb and cardiovascular manifestations. Consistent with the systemic nature of atherosclerosis, polyvascular disease is common in patients with PAD. 16 In the REACH registry, 61% of PAD patients had concomitant coronary artery disease (CAD) and/or cerebrovascular disease. 16 Thus, the presence of PAD portends a high risk for subsequent cardiovascular events. A meta-analysis of over 48,000 participants in population-based cohort studies demonstrated that a low ankle-brachial index (ABI) predicted a 2-fold risk of death, cardiovascular death, and major coronary events at all ranges of the Framingham Risk Score. 4 Further, the elevated risk of cardiovascular events is present in both symptomatic and asymptomatic patients. 17 Patients with atherosclerotic disease in more than 1 vascular territory have particularly poor outcomes. 6 In the over 5,000 Japanese T here is growing recognition of the effect of peripheral artery disease (PAD) on cardiovascular health. 1 Recent studies indicate that, globally, over 200 million adults have PAD, 2,3 which is an expression of systemic atherosclerosis and well-established as heightening the risk for cardiovascular events. 4-6 The limb manifestations of PAD induce considerable suffering. Patients with PAD experience intermittent claudication, characterized as exertional leg pain that limits walking ability, and often times, disability. 7-9 Current medical therapies to reduce the burden of lower extremity symptoms in patients with PAD are limited. Revascularization by endovascular intervention or surgical reconstruction is used to treat lifestyle-limiting claudication if patients do not respond adequately to medical therapy including exercise training. Indeed, lower extremity revascularization with endovascular approaches has undergone a dramatic increase in use. 10 Though endovascular therapy improves blood flow and function, there are significant associated risks, and durability may be limited, especially in infrainguinal disease. Abundant evidence demonstrates the benefits of exercise therapy in claudication, yet the mechanisms underlying the beneficial effects remain incompletely defined. 11 Thus, ...

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MicroRNA-93 Controls Perfusion Recovery After Hindlimb Ischemia by Modulating Expression of Multiple Genes in the Cell Cycle Pathway

Cited by 91 publications

References 34 publications

Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia

Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 Increases Neovascularization and Blood Flow Recovery After Ischemia

The regulatory role of microRNAs in angiogenesis‐related diseases

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

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