Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis

Welten, S.; Jong, Rob C. M. de; Wezel, Anouk; Vries, Margreet R. de; Boonstra, Martin C.; Parma, Laura; Jukema, J. Wouter; Sluis, Tetje C. van der; Arens, Ramon; Bot, Ilze; Agrawal, Sudhir; Quax, Paul H.A.; Nossent, A. Yaël

doi:10.1016/j.atherosclerosis.2017.04.011

Cited by 33 publications

(35 citation statements)

References 32 publications

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“…As ‘snoRnome-wide’ screening methods are not yet readily available, we selected a specific subset of snoRNAs and measured these by rt/qPCR, in order to determine whether or not snoRNAs may be suitable as biomarkers for either exercise or muscle recovery. We selected seven snoRNAs that are expressed from a single gene locus, 14q32, which also encodes 54 microRNA genes, including miR-495-3p, that we know are involved in angiogenesis and vascular remodeling ( Welten et al, 2014 , 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

et al. 2018

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Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non-coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR-193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker.

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Section: Resultsmentioning

confidence: 99%

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

et al. 2018

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“…In another study, miR-495 was thus shown to not only contribute to atherosclerotic lesion formation, but also plaque stability in ApoE −/− mice. Inhibition of miR-495 reduced intimal hyperplasia and decreased accelerated atherosclerosis and plasma cholesterol levels (83). A recent study revealed that activation of the NLRP3 inflammasome occurred after cerebral I/R, suggesting that initially microglia are the main source of activated NLRP3 inflammasomes, and in the later stages, the NLRP3 inflammasome is activated within neurons and vascular EC (84).…”

Section: Nlrp3 and Cvdsmentioning

confidence: 99%

Regulatory Mechanisms of the NLRP3 Inflammasome, a Novel Immune-Inflammatory Marker in Cardiovascular Diseases

Gao

et al. 2019

Front. Immunol.

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The nod-like receptor family pyrin domain containing 3 (NLRP3) is currently the most widely studied inflammasome and has become a hot topic of recent research. As a macromolecular complex, the NLRP3 inflammasome is activated to produce downstream factors, including caspase-1, IL-1β, and IL-18, which then promote local inflammatory responses and induce pyroptosis, leading to unfavorable effects. A growing number of studies have examined the relationship between the NLRP3 inflammasome and cardiovascular diseases (CVDs). However, some studies have shown that the NLRP3 inflammasome is not involved in the occurrence of certain diseases. Therefore, identifying the mechanism of action of the NLRP3 inflammasome and its potential involvement in the pathological process of disease progression is of utmost importance. This review discusses the mechanisms of NLRP3 inflammasome activation and the relationship between the inflammasome and CVDs, including coronary atherosclerosis, myocardial ischemia/reperfusion, cardiomyopathies, and arrhythmia, as well as CVD-related treatments.

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“…For example, inhibition of miR-329, miR-494, miR-487b, and miR-495 in mice stimulated neovascularization after hind limb ischemia (16), but inhibition of miR-494 in mice also decreased atherosclerosis and increased plaque stability (17). Moreover, inhibition of miR-495 reduced accelerated atherosclerosis and intimal hyperplasia in mice (18). Furthermore, miR-487b plays a role in angiotensin II-induced aneurysm formation in rats (19).…”

Section: Introductionmentioning

confidence: 99%

miRMap: Profiling 14q32 microRNA Expression and DNA Methylation Throughout the Human Vasculature

Goossens

Vries

Simons

et al. 2019

Front. Cardiovasc. Med.

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Aims: MicroRNAs are regulators of (patho)physiological functions with tissue-specific expression patterns. However, little is known about inter-vascular differences in microRNA expression between blood vessel types or vascular beds. Differences in microRNA expression could influence cardiovascular pathophysiology at specific sites in the vasculature. Therefore, we aimed to map expression profiles of vasoactive 14q32 microRNAs throughout the human vasculature, as well as expression of vasoactive target genes of the 14q32 microRNAs. Furthermore, we aimed to map the DNA methylation status of the 14q32 locus, which has been linked to cardiovascular disease. Methods and Results: We collected 109 samples from different blood vessels, dissected during general surgery. Expression of a representative set of 17 14q32 microRNAs was measured in each sample. All 17 microRNAs showed a unique expression pattern throughout the vasculature. 14q32 microRNA expression was highest in lower limb vessels and lowest in head and neck vessels. All 17 microRNAs were expressed more abundantly in arteries than in veins. Throughout the human vasculature, we observed trends toward an inverse correlation between expression levels of the 14q32 microRNAs and their vasoactive target genes. DNA methylation of the 3 Differentially Methylated Regions (DMRs) along the 14q32 locus did not associate with primary or mature microRNA expression. However, hyper-methylation in venous coronary artery bypass grafts compared to arterial bypass grafts was observed in the Intergenic-DMR and MEG3-DMR. In patients with end-stage peripheral arterial disease we found differential DNA methylation throughout all DMRs in their lower limb veins. These findings were confirmed in a mouse model for vein-graft disease in which we found regulated 14q32 DNA methylation during the active phase of vascular remodeling. In ischemic tissues of a murine hind limb ischemia model we observed an increase in DNA methylation associated with increased ischemia over time. Conclusions: We show that 14q32 microRNAs are abundantly expressed in the human vasculature and that expression differs significantly between different blood vessels. 14q32 DNA methylation also varies throughout the vasculature and is associated with vascular health, independently of microRNA levels. These findings could have important implications for future research and for future site-specific targeting of epigenetics-based therapeutics.

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Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis

Cited by 33 publications

References 32 publications

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

Regulatory Mechanisms of the NLRP3 Inflammasome, a Novel Immune-Inflammatory Marker in Cardiovascular Diseases

miRMap: Profiling 14q32 microRNA Expression and DNA Methylation Throughout the Human Vasculature

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