The Krüppel-like Factor 15 as a Molecular Link between Myogenic Factors and a Chromosome 4q Transcriptional Enhancer Implicated in Facioscapulohumeral Dystrophy

AbstractVascular calcification (VC) is highly prevailing in cardiovascular disease, diabetes mellitus, and chronic kidney disease and, when present, is associated with cardiovascular events and mortality. The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is regarded as the foundation for mediating VC. Related transcriptional enhancer factor (RTEF-1), also named as transcriptional enhanced associate domain (TEAD) 4 or transcriptional enhancer factor-3 (TEF-3), is a nuclear transcriptional factor with a potent effect on cardiovascular diseases, apart from its oncogenic role in the canonical Hippo pathway. However, the role and mechanism of RTEF-1 in VC, particularly in calcification of VSMCs, are poorly understood. Our results showed that RTEF-1 was reduced in calcified VSMCs. RTEF-1 significantly ameliorated β-glycerophosphate (β-GP)-induced VSMCs calcification, as detected by alizarin red staining and calcium content assay. Also, RTEF-1 reduced alkaline phosphatase (ALP) activity and decreased expressions of osteoblast markers such as Osteocalcin and Runt-related transcription factor-2 (Runx2), but increased expression of contractile protein, including SM α-actin (α-SMA). Additionally, RTEF-1 inhibited β-GP-activated Wnt/β-catenin pathway which plays a critical role in calcification and osteogenic differentiation of VSMCs. Specifically, RTEF-1 reduced the levels of Wnt3a, p-β-catenin (Ser675), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β (Ser9), but increased the levels of p-β-catenin (Ser33/37). Also, RTEF-1 increased the ratio of p-β-catenin (Ser33/37) to β-catenin proteins and decreased the ratio of p-GSK-3β (Ser9) to GSK-3β protein. LiCl, a Wnt/β-catenin signaling activator, was observed to reverse the protective effect of RTEF-1 overexpression on VSMCs calcification induced by β-GP. Accordingly, Dickkopf-1 (Dkk1), a Wnt antagonist, attenuated the role of RTEF-1 deficiency in β-GP-induced VSMCs calcification. Taken together, we concluded that RTEF-1 ameliorated β-GP-induced calcification and osteoblastic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling pathway.

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Effect of wing scalloping mutations on cut expression and sense organ differentiation in the Drosophila wing margin.

Genetics ◽

10.1093/genetics/131.2.353 ◽

1992 ◽

Vol 131 (2) ◽

pp. 353-363 ◽

Cited By ~ 4

Author(s):

J Jack ◽

Y DeLotto

Keyword(s):

Sense Organ ◽

Epidermal Cells ◽

Additive Effect ◽

Mutant Phenotype ◽

Wing Margin ◽

Transcriptional Enhancer ◽

Organ Differentiation ◽

Notch Activity ◽

Neural Fate ◽

Drosophila Wing

Abstract A number of wing scalloping mutations have been examined to determine their effects on the mutant phenotype of cut mutations and on the expression of the Cut protein. The mutations fall into two broad classes, those which interact synergistically with weak cut wing mutations to produce a more extreme wing phenotype than either mutation alone and those that have a simple additive effect with weak cut wing mutations. The synergistically interacting mutations are alleles of the Notch, Serrate and scalloped genes. These mutations affect development of the wing margin in a manner similar to the cut wing mutations. The mutations inactivate the cut transcriptional enhancer for the wing margin mechanoreceptors and noninnervated bristles and prevent differentiation of the organs. Surprisingly, reduction of Notch activity in the wing margin does not have the effect of converting epidermal cells to a neural fate as it does in other tissues of ectodermal origin. Rather, it prevents the differentiation of the wing margin mechanoreceptors and noninnervated bristles.

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Pain location and intensity impacts function in persons with myotonic dystrophy type 1 and facioscapulohumeral dystrophy with chronic pain

Muscle & Nerve ◽

10.1002/mus.24079 ◽

2014 ◽

Vol 49 (6) ◽

pp. 900-905 ◽

Cited By ~ 14

Author(s):

Jordi Miró ◽

Kevin J. Gertz ◽

Gregory T. Carter ◽

Mark P. Jensen

Keyword(s):

Chronic Pain ◽

Myotonic Dystrophy ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Facioscapulohumeral Dystrophy ◽

Pain Location

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Oxidative Stress-Dependent Impairment of Cardiac-Specific Transcription Factors in Experimental Diabetes

Endocrinology ◽

10.1210/en.2006-0728 ◽

2006 ◽

Vol 147 (12) ◽

pp. 5967-5974 ◽

Cited By ~ 73

Author(s):

Manuela Aragno ◽

Raffaella Mastrocola ◽

Claudio Medana ◽

Maria Graziella Catalano ◽

Ilenia Vercellinatto ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Left Ventricle ◽

Nuclear Factor Κb ◽

Diabetic Rats ◽

Nuclear Factor ◽

Downstream Signaling ◽

Zdf Rats ◽

Myogenic Factors ◽

Age Receptors

Oxidative stress plays a key role in the pathogenesis of diabetic cardiomyopathy, which is characterized by myocyte loss and fibrosis, finally resulting in heart failure. The study looked at the downstream signaling whereby oxidative stress leads to reduced myocardial contractility in the left ventricle of diabetic rats and the effects of dehydroepiandrosterone (DHEA), which production is suppressed in the failing heart and prevents the oxidative damage induced by hyperglycemia in several experimental models. DHEA was given orally at a dose of 4 mg/rat per day for 21 d to rats with streptozotocin (STZ)-induced diabetes and genetic diabetic-fatty (ZDF) rats. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, cardiac myogenic factors, and myosin heavy-chain gene expression were determined in the left ventricle of treated and untreated STZ-diabetic rats and ZDF rats. Oxidative stress induced by chronic hyperglycemia increased AGE and AGE receptors and led to activation of the pleoitropic transcription factor nuclear factor-κB. Nuclear factor-κB activation triggered a cascade of signaling, which finally led to the switch in the cardiac myosin heavy-chain (MHC) gene expression from the α-MHC isoform to the β-MHC isoform. DHEA treatment, by preventing the activation of the oxidative pathways induced by hyperglycemia, counteracted the enhanced AGE receptor activation in the heart of STZ-diabetic rats and ZDF rats and normalized downstream signaling, thus avoiding impairment of the cardiac myogenic factors, heart autonomic nervous system and neural crest derivatives (HAND) and myogenic enhancer factor-2, and the switch in MHC gene expression, which are the early events in diabetic cardiomyopathy.

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