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Caroline Cheng - One of the best experts on this subject based on the ideXlab platform.
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microRNA 132 212 family enhances arteriogenesis after hindlimb ischaemia through modulation of the ras mapk pathway
Journal of Cellular and Molecular Medicine, 2015Co-Authors: Zhiyong Lei, Imo E. Hoefer, Sebastian Grundmann, Alain Van Mil, Maarten M Brandt, Michiel Smits, Hamid El Azzouzi, Taro Fukao, Caroline ChengAbstract:Arteriogenesis is a complicated process induced by increased local shear-and radial wall-stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR-132/212 expression was significantly upregulated after occlusion of the femoral artery. miR-132/212 knockout (KO) mice display a slower perfusion recovery after hind-limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR-132/212 KO mice compared to WT, it can be stimulated with exogenous miR-132, a dominant member of the miR-132/212 family. Moreover, in in vitro pericyte-endothelial co-culture cell assays, overexpression of miR-132 and mir-212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR-132/212 may exert their effects by enhancing the Ras-Mitogen-activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR-132/212 cluster promotes arteriogenesis by modulating Ras-MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1.
Anton Jan Van Zonneveld - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Silencing of microRNA-132 Reduces Blood Glucose and Improves Insulin Secretion
Nucleic Acid Therapeutics, 2019Co-Authors: Roel Bijkerk, Johanne H. Ellenbroek, Yu Wah Au, Maaike Hanegraaf, Jonathan L. S. Esguerra, Eelco J.p. De Koning, Lena Eliasson, Anton Jan Van ZonneveldAbstract:Dysfunctional insulin secretion is a hallmark of type 2 diabetes (T2D). Interestingly, several islet microRNAs (miRNAs) are upregulated in T2D, including miR-132. We aimed to investigate whether in vivo treatment with antagomir-132 lowers expression of miR-132 in islets thereby improving insulin secretion and lowering blood glucose. Mice injected with antagomir-132 for 24 h, had reduced expression of miR-132 expression in islets, decreased blood glucose, and increased insulin secretion. In isolated human islets treated with antagomir-132, insulin secretion from four of six donors increased. Target prediction coupled with analysis of miRNA-messenger RNA expression in human islets revealed DESI2, ARIH1, SLC25A28, DIAPH1, and FOXA1 to be targets of miR-132 that are conserved in both species. Increased expression of these targets was validated in mouse islets after antagomir-132 treatment. In conclusion, we identified a post-transcriptional role for miR-132 in insulin secretion, and demonstrated that systemic antagomir-132 treatment in mice can be used to improve insulin secretion and reduce blood glucose in vivo. Our study is a first step towards utilizing antagomirs as therapeutic agents to modulate islet miRNA levels to improve beta cell function.
Roel Bijkerk - One of the best experts on this subject based on the ideXlab platform.
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microRNA-132 regulates salt-dependent steady-state renin levels in mice.
Communications Biology, 2020Co-Authors: Anton Jan Van Zonneveld, Wendy Stam, Sharon Van Gelderen, Joris I. Rotmans, Peter M. T. Deen, Ton J. Rabelink, Roel BijkerkAbstract:The body's salt and fluid balance is regulated by the renin-angiotensin-aldosterone system. Generation of prostaglandin-E2 (PGE2) in a cyclo-oxygenase-2 (COX-2)-dependent manner in the macula densa, the salt-sensing cells of the kidney, plays a dominant role in renin regulation. Here we show that miR-132 directly targets Cox-2 and affects subsequent PGE2 and renin levels. MiR-132 is induced and reduced by low- and high salt treatment, respectively, in a p38- and ERK1/2-independent and CREB- and salt inducible kinase-dependent manner. Silencing of miR-132 in mice increases macula densa COX-2 expression and elevates PGE2 and renin levels, which are abrogated by the selective COX-2-inhibitor Celecoxib. Furthermore, a low or high salt diet induces and reduces macula densa miR-132 expression, while low salt diet combined with silencing miR-132 further increases renin levels. Taken together, we demonstrate a posttranscriptional regulatory role for salt-dependent miR-132 in fine-tuning the steady-state levels of renin.
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In Vivo Silencing of microRNA-132 Reduces Blood Glucose and Improves Insulin Secretion
Nucleic Acid Therapeutics, 2019Co-Authors: Roel Bijkerk, Johanne H. Ellenbroek, Yu Wah Au, Maaike Hanegraaf, Jonathan L. S. Esguerra, Eelco J.p. De Koning, Lena Eliasson, Anton Jan Van ZonneveldAbstract:Dysfunctional insulin secretion is a hallmark of type 2 diabetes (T2D). Interestingly, several islet microRNAs (miRNAs) are upregulated in T2D, including miR-132. We aimed to investigate whether in vivo treatment with antagomir-132 lowers expression of miR-132 in islets thereby improving insulin secretion and lowering blood glucose. Mice injected with antagomir-132 for 24 h, had reduced expression of miR-132 expression in islets, decreased blood glucose, and increased insulin secretion. In isolated human islets treated with antagomir-132, insulin secretion from four of six donors increased. Target prediction coupled with analysis of miRNA-messenger RNA expression in human islets revealed DESI2, ARIH1, SLC25A28, DIAPH1, and FOXA1 to be targets of miR-132 that are conserved in both species. Increased expression of these targets was validated in mouse islets after antagomir-132 treatment. In conclusion, we identified a post-transcriptional role for miR-132 in insulin secretion, and demonstrated that systemic antagomir-132 treatment in mice can be used to improve insulin secretion and reduce blood glucose in vivo. Our study is a first step towards utilizing antagomirs as therapeutic agents to modulate islet miRNA levels to improve beta cell function.
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Silencing of microRNA-132 reduces renal fibrosis by selectively inhibiting myofibroblast proliferation
Kidney International, 2016Co-Authors: Roel Bijkerk, Ton J. Rabelink, Coen Van Solingen, Ruben G. De Bruin, Eric P. Van Der Veer, Janine M. Van Gils, Jacques M.g.j. Duijs, Benjamin D. Humphreys, Anton Jan Van ZonneveldAbstract:Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of α-smooth muscle actin (α-SMA) positive myofibroblasts. Here we sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. Kidney fibrosis was induced in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation, whereas miR-132 was only 2.5-fold up in total kidney lysates (both in obstructive and ischemia-reperfusion injury). MiR-132 silencing during obstruction decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, Western blot, and qRT-PCR confirmed a similar decrease in interstitial α-SMA + cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro . Indeed, antagomir-132–treated mice displayed a reduction in the number of proliferating Ki67 + interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in Ki67 + epithelial cells, as well as increased phospho-RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Additional pathway and gene expression analyses suggest miR-132 coordinately regulates genes involved in TGF-β signaling (Smad2/Smad3), STAT3/ERK pathways, and cell proliferation (Foxo3/p300). Thus, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy.
Tilde Eskildsen - One of the best experts on this subject based on the ideXlab platform.
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the microRNA 132 212 family fine tunes multiple targets in angiotensin ii signalling in cardiac fibroblasts
Journal of the Renin-Angiotensin-Aldosterone System, 2015Co-Authors: Tilde Eskildsen, Mikael Schneider, Maria B. Sandberg, Vibe Skov, Hasse Bronnum, Mads Thomassen, Torben A Kruse, Ditte Caroline AndersenAbstract:Introduction: microRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT1R signalling. However, the miR-132/212 targets in the heart remain unknown. Materials and methods: To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. Results: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors, signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways. Conclusion: We here report novel insight of an extensive network of molecular pathways that fine-tuned by miR- 132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function.
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angiotensin ii regulates microRNA 132 212 in hypertensive rats and humans
International Journal of Molecular Sciences, 2013Co-Authors: Tilde Eskildsen, Pia Jeppesen, Mikael Schneider, Anne Yael Nossent, Maria B. Sandberg, Charlotte Harken Jensen, Maria Lyck Hansen, Niels Marcussen, Pernille Laerkegaard B Hansen, Lars Melholt RasmussenAbstract:microRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are emerging as key regulators in cardiovascular development and disease. MiRNAs are involved in cardiac hypertrophy, heart failure and remodeling following cardiac infarction; however, miRNAs involved in hypertension have not been thoroughly investigated. We have recently reported that specific miRNAs play an integral role in Angiotensin II receptor (AT1R) signaling, especially after activation of the Gαq signaling pathway. Since AT1R blockers are widely used to treat hypertension, we undertook a detailed analysis of potential miRNAs involved in Angiotensin II (AngII) mediated hypertension in rats and hypertensive patients, using miRNA microarray and qPCR analysis. The miR-132 and miR-212 are highly increased in the heart, aortic wall and kidney of rats with hypertension (159 ± 12 mm Hg) and cardiac hypertrophy following chronic AngII infusion. In addition, activation of the endothelin receptor, another Gαq coupled receptor, also increased miR-132 and miR-212. We sought to extend these observations using human samples by reasoning that AT1R blockers may decrease miR-132 and miR-212. We analyzed tissue samples of mammary artery obtained from surplus arterial tissue after coronary bypass operations. Indeed, we found a decrease in expression levels of miR-132 and miR-212 in human arteries from bypass-operated patients treated with AT1R blockers, whereas treatment with β-blockers had no effect. Taken together, these data suggest that miR-132 and miR-212 are involved in AngII induced hypertension, providing a new perspective in hypertensive disease mechanisms.
Vivianna M. Van Deerlin - One of the best experts on this subject based on the ideXlab platform.
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tmem106b the risk gene for frontotemporal dementia is regulated by the microRNA 132 212 cluster and affects progranulin pathways
The Journal of Neuroscience, 2012Co-Authors: Alice Chenplotkin, Travis L. Unger, Michael D. Gallagher, Emily Bill, Linda K. Kwong, Johanna I. Busch, Sebastian Akle, Murray Grossman, Laura A Volpicellidaley, Vivianna M. Van DeerlinAbstract:Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene ( GRN ) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with TMEM106B ; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3′UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.
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tmem106b the risk gene for frontotemporal dementia is regulated by the microRNA 132 212 cluster and affects progranulin pathways
The Journal of Neuroscience, 2012Co-Authors: Alice Chenplotkin, Michael D. Gallagher, Emily Bill, Linda K. Kwong, Johanna I. Busch, Sebastian Akle, Murray Grossman, Laura A Volpicellidaley, Travis Unger, Vivianna M. Van DeerlinAbstract:Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3'UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.