MicroRNAs Are Essential for Stretch-induced Vascular Smooth Muscle Contractile Differentiation via MicroRNA (miR)-145-dependent Expression of L-type Calcium Channels

Turczyńska, Karolina M.; Sadegh, Mardjaneh Karbalaei; Hellstrand, Per; Swärd, Karl; Albinsson, Sebastian

doi:10.1074/jbc.m112.341073

Cited by 55 publications

(79 citation statements)

References 45 publications

(70 reference statements)

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“…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: 99%

“…We have previously demonstrated that actin polymerization is crucial for stretchinduced contractile differentiation in vascular smooth muscle (21)(22)(23)(24). Further, we reported that important regulators of smooth muscle differentiation, such as the small non-coding microRNA miR-145, promotes actin polymerization and that this effect is required for the regulation of contractile smooth muscle genes (25)(26)(27). However, the impact of actin polymerization on smooth muscle gene expression in the context of diabetic vascular disease has not yet been explored.…”

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confidence: 99%

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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: No Diabetesmentioning

confidence: 99%

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confidence: 99%

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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“…The relative abundance of mRNA was calculated after normalisation to the geometric mean of two internal control genes (Rps29 and Rn18s; Vandesompele et al 2002, Ferguson et al 2010. Qiagen miScript kits, reagents and primers were used to analyse miRNAs (Turczynska et al 2012). Each sample was analysed in duplicates.…”

Section: Rna and Mirna Preparation And Quantitative Real-time Pcrmentioning

confidence: 99%

LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues

Gormand¹,

Berggreen²,

Amar³

et al. 2014

Journal of Molecular Endocrinology

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cAMP-response element-binding protein (CREB) is required for the induction of adipogenic transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs). Interestingly, it is known from studies in other tissues that LKB1 and its substrates AMP-activated protein kinase (AMPK) and salt-inducible kinases (SIKs) negatively regulate gene expression by phosphorylating the CREB co-activator CRTC2 and class IIa histone deacetylases (HDACs), which results in their exclusion from the nucleus where they co-activate or inhibit their targets. In this study, we show that AMPK/SIK signalling is acutely attenuated during adipogenic differentiation of 3T3-L1 preadipocytes, which coincides with the dephosphorylation and nuclear translocation of CRTC2 and HDAC4. When subjected to differentiation, 3T3-L1 preadipocytes in which the expression of LKB1 was stably reduced using shRNA (Lkb1-shRNA), as well as Lkb1-knockout mouse embryonic fibroblasts (Lkb1 K/K MEFs), differentiated more readily into adipocyte-like cells and accumulated more triglycerides compared with scrambled-shRNA-expressing 3T3-L1 cells or Wt MEFs. In addition, the phosphorylation of CRTC2 and HDAC4 was reduced, and the mRNA expression of adipogenic transcription factors Cebpa, peroxisome proliferator-activated receptor g (Pparg) and adipocyte-specific proteins such as hormone-sensitive lipase (HSL), fatty acid synthase (FAS), aP2, GLUT4 and adiponectin was increased in the absence of LKB1. The mRNA and protein expression of Ddit3/CHOP10, a dominant-negative member of the C/EBP family, was reduced in Lkb1-shRNA-expressing cells, providing a potential mechanism for the up-regulation of Pparg and Cebpa expression. These results support the hypothesis that LKB1 signalling keeps preadipocytes in their non-differentiated form.

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“…12,84,[92][93][94][95][96][97] Similarly, a large number of microRNAs are implicated in vascular phenotypes ranging from pulmonary hypertension to aortic aneurysm. 77,79,[98][99][100][101][102][103][104][105][106][107] For example, microRNA-145 was recently shown to be upregulated in the lung tissue of patients with pulmonary hypertension and might be a contributing factor to the pathogenesis of pulmonary hypertension. 108 MicroRNA-10, microRNA-15a, microRNA-16, microRNA-26a, microR-NA-223, and microRNA-663 are involved in angiogenesis and regulate vascular smooth muscle and endothelial cell phenotypes.…”

Section: Micrornasmentioning

confidence: 99%

Recent Developments in Cardiovascular Genetics and Genomics

Marian

2014

Circulation Research

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Recent Developments in Cardiovascular Research:The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that these "Recent Developments" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. -The Editors

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MicroRNAs Are Essential for Stretch-induced Vascular Smooth Muscle Contractile Differentiation via MicroRNA (miR)-145-dependent Expression of L-type Calcium Channels

Cited by 55 publications

References 45 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

LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues

Recent Developments in Cardiovascular Genetics and Genomics

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