Micro<scp>RNA</scp> let‐7g possesses a therapeutic potential for peripheral artery disease

Hsu, Po‐Yuan; Hsi, Edward; Wang, Tzu-Ming; Lin, Ruey‐Tay; Liao, Yi‐Chu; Juo, Suh‐Hang Hank

doi:10.1111/jcmm.12997

Cited by 22 publications

(18 citation statements)

References 29 publications

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“…PAD affects ~20% of the population aged >55 years, worldwide (3). The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) determined that the prevalence of asymptomatic PAD is ~3–10% and is increasing to 15–20% in people aged >70 years worldwide (4). Critical limb ischemia (CLI) is the most severe clinical manifestation of PAD and may cause intermittent claudication, gangrene and foot ulcers (5).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

et al. 2019

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As an atherosclerotic disease, the process of peripheral arterial disease (PAD) is complicated and includes the abnormal proliferation of vascular smooth muscle. The current study aimed to determine the role of microRNA-15b (miR-15b) in the development of PAD and its associated mechanisms. Human vascular smooth muscle cells (hVSMCs) were used in the current study. To assess the effects of miR-15b on hVSMCs, miR-15b was up- or downregulated in hVSMCs using miR-15b mimics or miR-15b inhibitors respectively. Cell viability, migration and apoptosis were then determined via MTT, transwell and flow cytometry assays, respectively. TargetScan bioinformatics software was utilized to predict the targets of miR-15b, and the binding sites between insulin growth factor 1 receptor (IGF1R) and miR-15b were confirmed by dual-luciferase reporter assay. The results reveled that the miR-15b mimic significantly reduced hVSMC cell viability and migration, and promoted cell apoptosis. However, the opposite effect was observed following miR-15b inhibitor transfection. It was also determined that miR-15b directly targeted IGF1R and negatively regulated its expression in hVSMCs. Additionally, the results demonstrated that the miR-15b mimic inhibited the PI3K/AKT signaling pathway in hVSMCs, whereas the miR-15b inhibitor promoted it. Furthermore, the results indicated that the effect of the miR-15b mimic on hVSMCs was reversed by IGF1R overexpression. In conclusion, the data indicated that miR-15b participated in the occurrence and development of PAD by modulating hVSMC proliferation, apoptosis and migration via the regulation of IGF1R expression.

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Section: Introductionmentioning

confidence: 99%

MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

et al. 2019

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“…We recently showed that let-7g can reduce atherosclerotic change by improving endothelial functions and by reducing oxLDL uptake by VSMC and endothelial cells [ 12 , 13 , 26 ]. Here we demonstrated an additional role of let-7g in macrophages, which further supports the importance of let-7g in maintaining vascular health.…”

Section: Discussionmentioning

confidence: 99%

Let-7g suppresses both canonical and non-canonical NF-κB pathways in macrophages leading to anti-atherosclerosis

et al. 2017

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Transformation of macrophages to foam cells contributes to atherosclerosis. Here, we report that let-7g reduces macrophage transformation and alleviates foam cell apoptosis by suppressing both canonical and non-canonical NF-κB pathways. In the canonical pathway, let-7g inhibits phosphorylation of IKKβ and IκB, down-regulates SREBF2 and miR-33a, and up-regulates ABCA1. In the non-canonical pathway, let-7g directly knocks down MEKK1, IKKα and ablates IKKα phosphorylation. Let-7g's effects in macrophages can be almost completely blocked by inactivation of NF-κB signaling, which suggests that let-7g's effects are primarily mediated through the suppression of NF-κB pathways. NF-κB has been reported to directly activate lin28 transcription, and lin28 is a well-known negative regulator for let-7 biogenesis. Therefore, there is negative feedback between NF-κB and let-7g. Additional macrophages-specific NF-κB knockout in the apoE deficiency mice reduces atherosclerotic lesion by 85%. Let-7g also suppresses p53-dependent apoptosis. Altogether, sufficient let-7g levels are important to prevent NF-κB over-activation in macrophages and to prevent atherosclerosis.

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“…A previous study by our group reported that let-7g directly targets and suppresses LOX-1 ( 25 ). Further studies by our group have reported that let-7g improves several endothelial functions by causing a decrease of senescence, inflammation and monocyte adhesion, and an increase of angiogenesis ( 12 , 25 , 26 ). The present study aimed to investigate whether let-7g also provides endothelial protection via a LOX-1-independent mechanism.…”

Section: Introductionmentioning

confidence: 87%

MicroRNA let-7g inhibits angiotensin II-induced endothelial senescence via the LOX-1-independent mechanism

Hsu

Lin

et al. 2018

Int J Mol Med

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Endothelial senescence leads to cell dysfunction, which in turn eventually results in cardiovascular disease. Identifying factors that regulate endothelial senescence may provide insight into the pathogenesis of aging. Insulin-like growth factor (IGF) signaling has a significant role in the physiology of endothelial cells (ECs). Overactivation of IGF signaling has been implicated in promoting the aging process. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) is a scavenger receptor that mediates the internalization of oxLDL into cells. Previous studies by our group have indicated that microRNA let-7g exerts an anti-aging effect on ECs and also suppresses LOX-1 expression. Since LOX-1 also induces the aging process, the present study we explored whether let-7g still exerts an anti-aging effect on ECs when LOX-1 is suppressed. Angiotensin II (Ang II) was used to induce senescence in ECs. It was revealed that Ang II significantly increased the expression of aging markers, including β-galactosidase, LOX-1, IGF1 and its receptor IGF1R. On the contrary, Ang II decreased the expression of the anti-aging gene sirtuin 1 (SIRT1). When LOX-1 was knocked down by small interfering RNA, let-7g still dose-dependently decreased the expression of β-galactosidase (β-gal), LOX-1, IGF1 and IGF1R, and SIRT1 was still upregulated. Using senescence-associated β-gal staining, it was confirmed that let-7g exerts a LOX-1-independent anti-aging effect on ECs. In conclusion, the present study demonstrated that let-7g has an anti-aging effect regardless of the presence or absence of LOX-1.

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MicroRNA let‐7g possesses a therapeutic potential for peripheral artery disease

Cited by 22 publications

References 29 publications

MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

Let-7g suppresses both canonical and non-canonical NF-κB pathways in macrophages leading to anti-atherosclerosis

MicroRNA let-7g inhibits angiotensin II-induced endothelial senescence via the LOX-1-independent mechanism

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