The 14q32 MicroRNA-487b Targets the Antiapoptotic Insulin Receptor Substrate 1 in Hypertension-Induced Remodeling of the Aorta

Nossent, A. Yaël; Eskildsen, Tilde V; Andersen, Lene; Bie, Peter; Brønnum, Hasse; Schneider, Mikael; Andersen, Ditte Caroline; Welten, S.; Jeppesen, Pia; Hamming, Jaap F.; Hansen, Jane Lindschou; Quax, Paul H.A.; Sheikh, Søren Paludan

doi:10.1097/sla.0b013e3182a6aac0

Cited by 39 publications

(30 citation statements)

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“…We previously confirmed the role of miR-487b in outward remodeling of the aorta, via targeting the prosurvival factor insulin receptor substrate 1 in vivo in rats and in vitro in human primary arterial cells. 26 Having only a single conserved neovascularization target gene, insulin receptor substrate 1, most likely explains the slightly more moderate effects of miR-487b inhibition on blood flow recovery and neovascularization compared with miR-329 and miR-494 inhibition. A recent study on the role of miR-487b in human lung cancer did confirm SUZ12, BMI1, WNT5A, and KRAS as direct targets for miR-487b.…”

Section: Discussionmentioning

confidence: 99%

“…miR-487b was the second-most significantly upregulated 14q32 microRNA (early responder). Although it was not identified in either RTP, we did previously report that miR-487b plays an important role in outward remodeling of the aorta, 26 and therefore we also included miR-487b in our further studies. Expression of these 4 14q32 microRNAs was measured in various murine tissues using reverse transcription quantitative polymerase chain reaction (Online Figure II).…”

Section: Microarraymentioning

confidence: 99%

“…We confirmed that miR-487b directly targets the vasoactive insulin receptor substrate 1 in the arterial wall, leading to increased survival of both smooth muscle cells and myofibroblasts. 26 For miR-329, we selected Tlr4, 27 Mef2a, [20][21][22] 33 and Tgfbr. 34 We used reverse transcription quantitative polymerase chain reaction to determine whether these genes were upregulated in the left adductor muscles of mice treated with the relevant GSOs.…”

Section: In Vivo Target Gene Regulationmentioning

confidence: 99%

“…None of the GSOs had effects on proliferation of smooth muscle cells ( Figure 8F), as we had previously shown for GSO-487b. 26 We performed an aortic ring assay to determine GSOinduced sprout formation ex vivo. We observed that inhibition of all 4 selected 14q32 microRNAs with GSOs led to increased sprout formation compared with GSO control (Figure 8G-8L).…”

Section: In Vitro Effects Of 14q32 Microrna Inhibitionmentioning

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

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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: Discussionmentioning

confidence: 99%

Section: Microarraymentioning

confidence: 99%

Section: In Vivo Target Gene Regulationmentioning

confidence: 99%

Section: In Vitro Effects Of 14q32 Microrna Inhibitionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

135

161

View full text Add to dashboard Cite

show abstract

“…It was also shown that miRNA-487b is upregulated by angiotensine II-induced hypertension and directly targets the vasoactive molecule insulin receptor substrate 1. Via downregulation of insulin receptor substrate 1, miR-487b directly influences survival of adventitial fibroblasts and medial smooth muscle cells under stress [115]. MiRNA-139-5p has been recently discovered having anticancer efficacy in different organs.…”

Section: Modulation Of Mirnas Associated To Preconditioning Protect Cmentioning

confidence: 99%

Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

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Mechanism of Insulin Action

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2024

Textbook of Diabetes

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The 14q32 MicroRNA-487b Targets the Antiapoptotic Insulin Receptor Substrate 1 in Hypertension-Induced Remodeling of the Aorta

Abstract: Angiotensin II-induced hypertension leads to upregulation of miR-487b, which targets IRS1. Via downregulation of IRS1, miR-487b can contribute to cell death and loss of adventitial and medial integrity during hypertension-induced vascular pathology.

Cited by 39 publications

References 25 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

Novel approaches of pharmacological preconditioning: the role of biglycan and miRNAs

Mechanism of Insulin Action

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