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The Effect of Hemodynamic Remodeling on the Survival of Arterialized Venous Flaps  [PDF]
Hede Yan, Jon Kolkin, Bin Zhao, Zhefeng Li, Shichao Jiang, Wei Wang, Zhen Xia, Cunyi Fan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079608
Abstract: Objective To evaluate the effect of hemodynamic remodeling on the survival status of the arterialized venous flaps (AVFs) and investigate the mechanism of this procedure. Materials and Methods Two 7 x 9 cm skin flaps in each rabbit (n=36) were designed symmetrically in the abdomen. The thoracoepigastric pedicle and one femoral artery were used as vascular sources. Four groups were included: Composite skin grafts group and arterial perfusion group were designed in one rabbit; AVF group and hemodynamic remodeling group by ligation of the thoracoepigastric vein in the middle were outlined in another rabbit. Flap viability, status of vascular perfusion and microvasculature, levels of epidermal metabolite and water content in each group were assessed. Results Highly congested veins and simple trunk veins were found using angiography in the AVF group; while a fairly uniform staining and plenty of small vessels were observed in the hemodynamic remodeling group. The metabolite levels of the remodeling group are comparable with those in the arterial perfusion group. There was no statistically significant difference in the percentage of flap survival between the arterial perfusion group and hemodynamic remodeling group; however, significant difference was seen between the AVF group and the hemodynamic remodeling group. Conclusions Under the integrated perfusion mode, the AVFs are in an over-perfusion and non-physiological hemodynamic state, resulting in unreliability and unpredictability in flap survival; under the separated perfusion mode produced by remodeling, a physiological-like circulation will be created and therefore, better flap survival can be expected.
Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle
Marlene Norrby, Kim Evertsson, Ann-Kristin Fj?llstr?m, Anna Svensson, Sven T?gerud
Journal of Molecular Signaling , 2012, DOI: 10.1186/1750-2187-7-7
Abstract: In denervated hypertrophic muscle expression of total Akt1, Akt2, GSK-3beta, p70S6K1 and rpS6 proteins increased 2–10 fold whereas total 4EBP1 protein remained unaltered. In denervated atrophic muscle Akt1 and Akt2 total protein increased 2–16 fold. A small increase in expression of total rpS6 protein was also observed with no apparent changes in levels of total GSK-3beta, 4EBP1 or p70S6K1 proteins. The level of phosphorylated proteins increased 3–13 fold for all the proteins in hypertrophic denervated muscle. No significant changes in phosphorylated Akt1 or GSK-3beta were detected in atrophic denervated muscle. The phosphorylation levels of Akt2, 4EBP1, p70S6K1 and rpS6 were increased 2–18 fold in atrophic denervated muscle.The results are consistent with increased Akt/mTOR signaling in hypertrophic skeletal muscle. Decreased levels of phosphorylated Akt (S473/S474) were not observed in denervated atrophic muscle and results downstream of mTOR indicate increased protein synthesis in denervated atrophic anterior tibial muscle as well as in denervated hypertrophic hemidiaphragm muscle. Increased protein degradation, rather than decreased protein synthesis, is likely to be responsible for the loss of muscle mass in denervated atrophic muscles.
MicroRNA-21 Regulates hTERT via PTEN in Hypertrophic Scar Fibroblasts  [PDF]
Hua-Yu Zhu, Chao Li, Wen-Dong Bai, Lin-Lin Su, Jia-Qi Liu, Yan Li, Ji-Hong Shi, Wei-Xia Cai, Xiao-Zhi Bai, Yan-Hui Jia, Bin Zhao, Xue Wu, Jun Li, Da-Hai Hu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097114
Abstract: Background As an important oncogenic miRNA, microRNA-21 (miR-21) is associated with various malignant diseases. However, the precise biological function of miR-21 and its molecular mechanism in hypertrophic scar fibroblast cells has not been fully elucidated. Methodology/Principal Findings Quantitative Real-Time PCR (qRT-PCR) analysis revealed significant upregulation of miR-21 in hypertrophic scar fibroblast cells compared with that in normal skin fibroblast cells. The effects of miR-21 were then assessed in MTT and apoptosis assays through in vitro transfection with a miR-21 mimic or inhibitor. Next, PTEN (phosphatase and tensin homologue deleted on chromosome ten) was identified as a target gene of miR-21 in hypertrophic scar fibroblast cells. Furthermore, Western-blot and qRT-PCR analyses revealed that miR-21 increased the expression of human telomerase reverse transcriptase (hTERT) via the PTEN/PI3K/AKT pathway. Introduction of PTEN cDNA led to a remarkable depletion of hTERT and PI3K/AKT at the protein level as well as inhibition of miR-21-induced proliferation. In addition, Western-blot and qRT-PCR analyses confirmed that hTERT was the downstream target of PTEN. Finally, miR-21 and PTEN RNA expression levels in hypertrophic scar tissue samples were examined. Immunohistochemistry assays revealed an inverse correlation between PTEN and hTERT levels in high miR-21 RNA expressing-hypertrophic scar tissues. Conclusions/Significance These data indicate that miR-21 regulates hTERT expression via the PTEN/PI3K/AKT signaling pathway by directly targeting PTEN, therefore controlling hypertrophic scar fibroblast cell growth. MiR-21 may be a potential novel molecular target for the treatment of hypertrophic scarring.
MicroRNA biogenesis and regulation of bone remodeling
Kristina Kapinas, Anne M Delany
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3325
Abstract: Transcription factors, RNA binding proteins, and microRNAs (miRNAs) are among the factors that must act coordinately to control gene expression networks important for cellular function [1]. Following transcription, mRNAs are subject to the processes of splicing, nuclear export, trafficking, and polyadenylation, followed by translation initiation and elongation. Each of these processes represents a point at which expression can be regulated, allowing for fine-tuning in response to changing environmental conditions. miRNAs are short (approximately 21-nucleotide) non-coding RNAs that regulate transcript localization, polyadenylation, and translation. miRNAs are direct negative regulators of gene expression that bind to specific sequences within a target mRNA [2,3].miRNAs were discovered as a result of studies aimed at identifying genes that mediate developmental transitions in Caenorhabditis elegans [4,5]. Recent years have seen significant advances in the miRNA field, including the characterization of the miRNA biogenesis pathway, identification of the mechanisms by which miRNAs regulate gene expression, and an appreciation of how families of miRNAs can regulate cellular processes and contribute to disease phenotypes.The goal of this review is to highlight our current understanding of miRNA biogenesis and mechanisms of action, and to summarize recent studies on the role of miRNAs in bone remodeling.The miRNA biogenesis pathway has several steps: transcription, pri-miRNA processing, transport to the cytoplasm, precursor miRNA (pre-miRNA) processing, strand selection, transcript targeting, and transcript fate (Figure 1). This rigorous, multistep processing pathway helps ensure that only RNAs with the correct structures and sequences are able to regulate gene expression.miRNA genes are found on every chromosome in humans, except for the Y chromosome. Like the promoters of protein-coding genes, miRNA promoters are regulated by epigenetics and by transcription factors. miR
Importance of hemodynamic factors in vascular remodeling of muscular elastic type in arterial hypertension  [PDF]
Melnikova L.V.
Saratov Journal of Medical Scientific Research , 2011,
Abstract: The research goal is to investigate the relationship between hemodynamic factors and parameters of remodeling of common carotid arteries. 102 patients with essential hypertension of l-ll stage (49 men, 53 women, average age 47,5±11,2 years, duration of hypertension 7,8±1,5 years) have been examined. The study has revealed the relation between blood flow velocity in the common carotid artery (CCA) and the parameters of vascular remodeling, depending on the degree of hypertension. With the increase in systolic blood pressure dilation of common carotid arteries has been observed, reducing the rate of blood flow and wall thickness of the intima-media complex, accompanied by increased stiffness of the vascular wall. The increase in systolic blood pressure is accompanied by decrease in the rate of blood flow and wall tension on the endothelium, which contributes to thickness of the intima-media complex and increases the rigidity of the vascular wall
MicroRNA-1 Downregulation Increases Connexin 43 Displacement and Induces Ventricular Tachyarrhythmias in Rodent Hypertrophic Hearts  [PDF]
Antonio Curcio, Daniele Torella, Claudio Iaconetti, Eugenia Pasceri, Jolanda Sabatino, Sabato Sorrentino, Salvatore Giampà, Mariella Micieli, Alberto Polimeni, Beverley J. Henning, Angelo Leone, Daniele Catalucci, Georgina M. Ellison, Gianluigi Condorelli, Ciro Indolfi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070158
Abstract: Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.
MicroRNA 21 Inhibits Left Ventricular Remodeling in the Early Phase of Rat Model with Ischemia-reperfusion Injury by Suppressing Cell Apoptosis
Yanjun Qin, Yueqing Yu, Hua Dong, Xiaohua Bian, Xuan Guo, Shimin Dong
International Journal of Medical Sciences , 2012,
Abstract: Objective: To determine the role of microRNA 21(miR-21) on left ventricular remodeling of rat heart with ischemia-reperfusion (I/R) injury and to investigate the underlying mechanism of miR-21 mediated myocardium protection. Methods: Rats were randomly divided into three groups: an I/R model group with Ad-GFP (Ad-GFP group), an I/R model group with Ad-miR-21 (Ad-miR-21 group) and a sham-surgery group. Changes in hemodynamic parameters were recorded at 1 week after I/R. Histological diagnosis was achieved by hematoxylin and eosin (H&E). Left ventricular (LV) dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells were measured. Primary cultures of neonatal rat cardiac ventricular myocytes were performed and cell ischemic injury was induced by hypoxia in a serum- and glucose-free medium, and reoxygenation (H/R).MiR-21 inhibitor and pre-miR-21 were respectively added to the culture medium for the miR-21 knockdown and for the miR-21 up-regulation. qRT-PCR was used to determine the miR-21 levels in cultured cells. Flow cytometry was performed to examine the cell apoptosis. Results: In the Ad-miR-21 group, LV dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells all significantly decreased compared with the Ad-GFP group. At 1 week after I/R, the Ad-miR-21 significantly improved LVSP, LV +dp/dtmax, LV dp/dtmin, and decreased heart rate (HR) and LVEDP compared with the Ad-GFP group. Compared with the Ad-GFP, the cell apoptotic rate significantly decreased in the Ad-miR-21 group. The miR-21 inhibitor exacerbated cardiac myocyte apoptosis and the pre-miR-21 decreased hypoxia/reoxygenation- induced cardiac myocyte apoptosis. Conclusions: Ad-miR-21 improves LV remodeling and decreases the apoptosis of myocardial cells, suggesting the possible mechanism by which Ad-miR-21 functions in protecting against I/R injury.
Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation
Ying Zhang,DeLi Dong,BaoFeng Yang
Science China Life Sciences , 2011, DOI: 10.1007/s11427-011-4241-3
Abstract: Atrial fibrillation (AF) remains one of the leading causes of morbidity and mortality in the world which are related to palpitations, fainting, congestive heart failure or stroke. The mechanism for atrial fibrillation has been identified as electrical remodeling, structure remodeling and intracellular calcium handling remodeling. microRNAs (miRNAs) have recently emerged as one of the important factors in regulating gene expression. So far, thousands of miRNA genes have been found in diverse animals with the function of regulating cell death, cell proliferation, haematopoiesis and even participate in the processing of cardiovascular disease. In this review, we summarize the mechanism of AF and the association of microRNAs network with AF. We provide a potential perspective of miRNAs as the therapeutic target for AF.
Pattern and degree of left ventricular remodeling following a tailored surgical approach for hypertrophic obstructive cardiomyopathy
Ismail El-Hamamsy,Karim Lekadir,Iacopo Olivotto,Ahmed El Guindy
Global Cardiology Science & Practice , 2012, DOI: 10.5339/gcsp.2012.9
Abstract: Background The role of a tailored surgical approach for hypertrophic cardiomyopathy (HCM) on regional ventricular remodelling remains unknown. The aims of this study were to evaluate the pattern, extent and functional impact of regional ventricular remodelling after a tailored surgical approach. Conclusion Following a tailored surgical relief of outflow obstruction for HCM, there is a marked regional reverse LV remodelling. These changes could have a significant impact on overall ventricular dynamics and function.
Decreased MicroRNA Is Involved in the Vascular Remodeling Abnormalities in Chronic Kidney Disease (CKD)  [PDF]
Neal X. Chen, Kraiwiporn Kiattisunthorn, Kalisha D. O'Neill, Xianming Chen, Ranjani N. Moorthi, Vincent H. Gattone, Matthew R. Allen, Sharon M. Moe
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064558
Abstract: Patients with CKD have abnormal vascular remodeling that is a risk factor for cardiovascular disease. MicroRNAs (miRNAs) control mRNA expression intracellularly and are secreted into the circulation; three miRNAs (miR-125b, miR-145 and miR-155) are known to alter vascular smooth muscle cell (VSMC) proliferation and differentiation. We measured these vascular miRNAs in blood from 90 patients with CKD and found decreased circulating levels with progressive loss of eGFR by multivariate analyses. Expression of these vascular miRNAs miR-125b, miR-145, and miR-155 was decreased in the thoracic aorta in CKD rats compared to normal rats, with concordant changes in target genes of RUNX2, angiotensin II type I receptor (AT1R), and myocardin. Furthermore, the expression of miR-155 was negatively correlated with the quantity of calcification in the aorta, a process known to be preceded by vascular de-differentiation in these animals. We then examined the mechanisms of miRNA regulation in primary VSMC and found decreased expression of miR-125b, 145, and 155 in VSMC from rats with CKD compared to normal littermates but no alteration in DROSHA or DICER, indicating that the low levels of expression is not due to altered intracellular processing. Finally, overexpression of miR-155 in VSMC from CKD rats inhibited AT1R expression and decreased cellular proliferation supporting a direct effect of miR-155 on VSMC. In conclusion, we have found ex vivo and in vitro evidence for decreased expression of these vascular miRNA in CKD, suggesting that alterations in miRNAs may lead to the synthetic state of VSMC found in CKD. The decreased levels in the circulation may reflect decreased vascular release but more studies are needed to confirm this relationship.
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