Stretch-Sensitive Down-Regulation of the miR-144/451 Cluster in Vascular Smooth Muscle and Its Role in AMP-Activated Protein Kinase Signaling

Turczyńska, Karolina M.; Bhattachariya, Anirban; Säll, Johanna; Göransson, Olga; Swärd, Karl; Hellstrand, Per; Albinsson, Sebastian

doi:10.1371/journal.pone.0065135

Cited by 34 publications

(30 citation statements)

References 41 publications

(46 reference statements)

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“…To confirm an increased glucose metabolism under hyperglycemic conditions in our model, we analyzed the regulation of AMPK/acetyl-CoA carboxylase signaling and found a significant decrease in AMPK activation under hyperglycemic conditions. However, in both cultured cells and intact blood vessels, activation of AMPK by AICAR results in a significant induction of smooth muscle marker expression (29). Thus, our previous data indicate that the effect of glucose on AMPK would rather counteract glucose-induced expression of contractile smooth muscle markers.…”

Section: Volume 291 • Number 7 • February 12 2016mentioning

confidence: 83%

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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: Volume 291 • Number 7 • February 12 2016mentioning

confidence: 83%

“…217004), as described previously (29). Purity and concentration were determined with an ND-1000 spectrophotometer (Nanodrop Technologies Inc., Wilmington, DE).…”

Section: Methodsmentioning

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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“…Recent studies have shown that miRNA are essential in stretch-induced differentiation of vSMCs 32–35 . In particular, miR-143 and miR-145 have been linked to promoting the differentiated state in vascular smooth muscle cells while miR-31 and miR-221/222 has been associated with the dedifferentiated/proliferative state 36 .…”

Section: Resultsmentioning

confidence: 99%

“…Several studies support that miRNA are essential in stretch-induced differentiation of vSMCs 32–35 . In particular the miR-143/145 cluster promotes the differentiated state 36 .…”

Section: Discussionmentioning

confidence: 95%

A novel system for studying mechanical strain waveform-dependent responses in vascular smooth muscle cells

et al. 2013

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While many studies have examined the effects mechanical forces on vSMCs, there is a limited understanding of how the different arterial strain waveforms that occur in disease and different vascular beds alter vSMC mechanotransduction and phenotype. Here, we present a novel system for applying complex, time-varying strain waveforms to cultured cells and use this system to understand how these waveforms can alter vSMC phenotype and signaling. We have developed a highly adaptable cell culture system that allows the application of mechanical strain to cells in culture and can reproduce the complex dynamic mechanical environment experienced by arterial cells in the body. Using this system, we examined whether the type of applied strain waveform altered phenotypic modulation of vSMCs by mechanical forces. Cells exposed to the brachial waveform had increased phosphorylation of AKT, EGR-1, c-Fos expression and cytoskeletal remodeling in comparison to cells treated with the aortic waveform. In addition, vSMCs exposed to physiological waveforms had adopted a more differentiated phenotype in comparison to those treated with static or sinusoidal cyclic strain, with increased expression of vSMC markers desmin, calponin and SM-22 as well as increased expression of regulatory miRNAs including miR-143, -145 and -221. Taken together, our studies demonstrate the development of a novel system for applying complex, timevarying mechanical forces to cells in culture. In addition, we have shown that physiological strain waveforms have powerful effects on vSMC phenotype.

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“…Although we demonstrated that miRNAs are essential for stretch‐induced contractile differentiation and calcium signaling in the vascular wall, the effects of stretch on miRNA expression in the intact vascular smooth muscle had not been studied at the time. We thus used the portal vein model to investigate stretch‐induced miRNA expression following 24 hours of organ culture . Our experience is that many miRNAs have a quite slow turnover, and 24 hours may therefore be considered an early time point of the effect of stretch on miRNA expression.…”

Section: Stretch‐induced Expression Of Mirnas In the Portal Veinmentioning

confidence: 99%

Stretch‐Dependent Smooth Muscle Differentiation in the Portal Vein—Role of Actin Polymerization, Calcium Signaling, and microRNAs

2014

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The mechanical forces acting on SMC in the vascular wall are known to regulate processes such as vascular remodeling and contractile differentiation. However, investigations to elucidate the underlying mechanisms of mechanotransduction in smooth muscle have been hampered by technical limitations associated with mechanical studies on pressurized small arteries, due primarily to the small amount of available tissue. The murine portal vein is a relatively large vessel showing myogenic tone that in many respects recapitulates the properties of small resistance vessels. Studies on stretched portal veins to elucidate mechanisms of mechanotransduction in the vascular wall have shown that stretch‐sensitive regulation of contractile differentiation is mediated via Rho‐activation and actin polymerization, while stretch‐induced growth is regulated by the MAPK pathway. In this review, we have summarized findings on mechanotransduction in the portal vein with focus on stretch‐induced contractile differentiation and the role of calcium, actin polymerization and miRNAs in this response.

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Stretch-Sensitive Down-Regulation of the miR-144/451 Cluster in Vascular Smooth Muscle and Its Role in AMP-Activated Protein Kinase Signaling

Cited by 34 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

A novel system for studying mechanical strain waveform-dependent responses in vascular smooth muscle cells

Stretch‐Dependent Smooth Muscle Differentiation in the Portal Vein—Role of Actin Polymerization, Calcium Signaling, and microRNAs

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