Induction of angiotensin-converting enzyme after miR-143/145 deletion is critical for impaired smooth muscle contractility

Dahan, Diana; Ekman, Mari; Larsson‐Callerfelt, Anna‐Karin; Turczyńska, Karolina M.; Boettger, Thomas; Braun, Thomas; Swärd, Karl; Albinsson, Sebastian

doi:10.1152/ajpcell.00250.2014

Cited by 31 publications

(27 citation statements)

References 41 publications

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“…Isometric Force Measurements-Aortic rings (1.5-2 mm in length) were mounted in a Mulvany myograph (610M, Danish Myo Technology) as described previously (31). After an equilibration period, cumulative concentration-response curves for serotonin (5-hydroxytryptamine; 5-HT) were generated.…”

Section: Methodsmentioning

confidence: 99%

“…The regulation of L-type calcium channel expression by miR-145 is in part mediated by direct interaction of miR-145 with its target CamKII␦ (26,66), which in turn affects the translocation of a transcriptional repressor called DREAM (67). In earlier studies, we found that knockdown of miR-145 or genetic deletion of the miR-143/145 cluster results in increased CamKII␦ expression and reduced expression of L-type calcium channels (26,31,65). Considering the sensitivity to L-type calcium channel verapamil, it is likely that reduced L-type calcium channel expression is involved in the diminished glucose-mediated transcription of contractile smooth muscle markers in miR-143/145 KO cells.…”

Section: No Diabetesmentioning

confidence: 96%

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Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Hien¹,

Turczyńska²,

Dahan³

et al. 2016

Journal of Biological Chemistry

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Both type 1 and type 2 diabetes are associated with increased risk of cardiovascular disease. This is in part attributed to the effects of hyperglycemia on vascular endothelial and smooth muscle cells, but the underlying mechanisms are not fully understood. In diabetic animal models, hyperglycemia results in hypercontractility of vascular smooth muscle possibly due to increased activation of Rho-kinase. The aim of the present study was to investigate the regulation of contractile smooth muscle markers by glucose and to determine the signaling pathways that are activated by hyperglycemia in smooth muscle cells. Microarray, quantitative PCR, and Western blot analyses revealed that both mRNA and protein expression of contractile smooth muscle markers were increased in isolated smooth muscle cells cultured under high compared with low glucose conditions. This effect was also observed in hyperglycemic Akita mice and in diabetic patients. Elevated glucose activated the protein kinase C and Rho/Rho-kinase signaling pathways and stimulated actin polymerization. Glucose-induced expression of contractile smooth muscle markers in cultured cells could be partially or completely repressed by inhibitors of advanced glycation end products, L-type calcium channels, protein kinase C, Rho-kinase, actin polymerization, and myocardin-related transcription factors. Furthermore, genetic ablation of the miR-143/145 cluster prevented the effects of glucose on smooth muscle marker expression. In conclusion, these data demonstrate a possible link between hyperglycemia and vascular disease states associated with smooth muscle contractility.Diabetes confers a 2-4-fold excess risk for a wide range of cardiovascular diseases, including macrovascular complications leading to coronary heart disease and ischemic stroke, as well as microvascular diseases, such as nephropathy and retinopathy (1, 2). Based on current trends, the rising incidence of diabetes (expected to reach 333 million people worldwide by 2025) will undoubtedly equate to increased cardiovascular mortality. Chronic hyperglycemia has long been recognized as an independent risk factor for cardiovascular disease (3, 4). Importantly, the progressive relationship between glucose levels and cardiovascular risk extends below the threshold for diabetes diagnosis (fasting plasma glucose Ն7.0 mmol/liter or 2-h plasma glucose Ն11.1 mmol/liter (2, 3)), and more recently, even transient hyper-and hypoglycemia have emerged as important determinants of cardiovascular disease (5). Despite the vast clinical and epidemiological experience linking blood glucose and poor glucose control to the development and progression of cardiovascular disease, the underlying molecular mechanisms leading to vascular dysfunction and disease are poorly understood (6).It has been well established that hyperglycemia results in vascular hyperreactivity in diabetic patients (7) and animal models (8 -10). Part of this effect may be attributed to a decrease in nitric oxide (NO) bioavailability as well as a reduced respon...

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Section: Methodsmentioning

confidence: 99%

Section: No Diabetesmentioning

confidence: 96%

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Hien¹,

Turczyńska²,

Dahan³

et al. 2016

Journal of Biological Chemistry

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“…Most notably, the miR-143/145 cluster is essential for vascular smooth muscle contractile differentiation and vascular function [33,34,[37][38][39][44][45][46].…”

Section: Several Of the Actin/mrtf-a-sensitive Mirnas Identified In Tmentioning

confidence: 99%

“…cluster, which is known to be enriched in smooth muscle and promote contractile smooth muscle differentiation [35][36][37][38][39]. However, to our knowledge, the transcriptional regulation of miRNAs by MRTF-A and actin dynamics has not been investigated previously in vascular smooth muscle, although multiple lines of evidence points towards a crucial role of actin/MRTF in vascular disease.…”

Section: Introductionmentioning

confidence: 97%

Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization

Alajbegovic

Turczyńska

Hien

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The dynamic properties of the actin cytoskeleton in smooth muscle cells play an important role in a number of cardiovascular disease states. The state of actin does not only mediate mechanical stability and contractile function but can also regulate gene expression via myocardin related transcription factors (MRTFs). These transcriptional co-activators regulate genes encoding contractile and cytoskeletal proteins in smooth muscle. Regulation of small noncoding microRNAs (miRNAs) by actin polymerization may mediate some of these effects. MiRNAs are short non-coding RNAs that modulate gene expression by post-transcriptional regulation of target messenger RNA.In this study we aimed to determine a profile of miRNAs that were 1) regulated by actin/MRTF-A, 2) associated with the contractile smooth muscle phenotype and 3) enriched in muscle cells. This analysis was performed using cardiovascular disease-focused miRNA arrays in both mouse and human cells. The potential clinical importance of actin polymerization in aortic aneurysm was evaluated using biopsies from mildly dilated human thoracic aorta in patients with stenotic tricuspid or bicuspid aortic valve.By integrating information from multiple qPCR based miRNA arrays we identified a group of five miRNAs (miR-1, miR-22, miR-143, miR-145 and miR-378a) that were sensitive to actin polymerization and MRTF-A overexpression in both mouse and human smooth muscle. With the exception of miR-22, these miRNAs were also relatively enriched in striated and/or smooth muscle containing tissues. Actin polymerization was found to be dramatically reduced in the aorta from patients with mild aortic dilations. This was associated with a decrease in actin/MRTF-regulated miRNAs.In conclusion, the transcriptional co-activator MRTF-A and actin polymerization regulated a subset of miRNAs in smooth muscle. Identification of novel miRNAs regulated by actin/MRTF-A may provide further insight into the mechanisms underlying vascular disease states, such as aortic aneurysm, as well as novel ideas regarding therapeutic strategies.

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“…miR-143 and -145 have been shown to regulate the differentiation and functions of smooth muscle cells in the vessel wall structure. An in vitro study examining vascular diseases indicated that vessel wall stress may cause lower expression of these miRNAs [34,35]. It was demonstrated that these miRNAs may be necessary for neointima formation in atherosclerosis [36].…”

Section: Micro-rnas In Cardiovascular Diseasesmentioning

confidence: 99%

Unknown Aspects of Well-known Cardiovascular Diseases: Identification of Novel miRNA Genes

Çeviker¹,

Bağcı²,

Yazkan³

2016

Ann Clin Anal Med

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ÖzetKodlanmayan küçük ribonükleik asit (miRNA)'lerin bulunması ve işlevlerinin tanımlanmasıyla, RNA'ların canlı yaşamı için çok önemli süreçlerde rol oynadıkları belirlenmiştir. miRNA'larda meydana gelen bozukluklar birçok hastalı-ğa yol açmaktadır. Beklendiği üzere kanserler, nörodejeneratif hastalıklar ve immün yetmezlik gibi hastalıklarla ilişkilendirilmiş ve son yıllarda yeni yapı-lan çalışmalarla kardiyovasküler hastalıklarla olan ilişkilileri gösterilmiştir. Bu miRNA'lar, yeni tedavi yaklaşımlarında hem hedef hem de araç olarak görül-mektedirler. İnsan genomundaki tüm miRNA'ların işlevlerinin aydınlatılmasıy-la yeni tedavi yaklaşımları geliştirilebilecektir. Bu derlemede, miRNA'ların kardiyovasküler hastalıklarla ilişkili olduğu kuvvetli çalışmalarla ispatlanan çeşit-leri, kardiyovasküler hastalıklarla olan ilişkileri, ve tanı-tedavi amaçlı kullanımlarıyla ilgili literatüre dayalı değerlendirme yapılmıştır. Anahtar KelimelerKardiyovasküler Hastalık; Ateroskleroz; Miyokard Enfarktüsü (MI); Mikro RNA

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Induction of angiotensin-converting enzyme after miR-143/145 deletion is critical for impaired smooth muscle contractility

Abstract: S. Induction of angiotensin converting enzyme after miR-143/145 deletion is critical for impaired smooth muscle contractility.

Cited by 31 publications

References 41 publications

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization

Unknown Aspects of Well-known Cardiovascular Diseases: Identification of Novel miRNA Genes

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