Abstract 271: A Novel Functional Role for Plasma miR-30d in Dyssynchronous Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Kirsty Danielson ◽  
Yonathan Melman ◽  
Bridget Simonson ◽  
Andreas Barth ◽  
Khalid Chakir ◽  
...  
Keyword(s):  
Heart Failure ◽  
Functional Role ◽  
Lateral Wall ◽  
Canine Model ◽  
Cardiac Resynchronization ◽  
Tissue Samples ◽  
Diagnostic Strategies ◽  
Qrt Pcr ◽  
Dyssynchronous Heart Failure

Introduction: We have previously shown that plasma miR-30d level is an independent predictor of echocardiographic response to cardiac resynchronization therapy (CRT) in patients with dyssynchronous heart failure (DHF). We now test the hypothesis that miR-30d is dynamically regulated in cardiomyocytes (CMs) and plays a functional role in DHF. Methods: miR-30d levels were assessed in a canine model of DHF and CRT using qRT-PCR, and potential miR-30d targets were identified using a bioinformatics approach. miR-30d targets were validated in the canine model and in CMs in culture. The regulation and functional role of miR-30d was investigated in CMs in culture using microscopy, western blotting and qRT-pCR. Results: miR-30d is enriched in the coronary sinus compared to peripheral blood in human patients, suggesting a cardiac origin (n=7, p<0.05). In tissue samples from the canine model of DHF, miR-30d levels are highest in the lateral wall, in concert with the greatest wall stress, and decreases with CRT (n=5, p<0.05). Bioinformatics analysis using differential gene expression data and in silico miR target prediction algorithms identified integrin and PI3/Akt signaling pathways as targets of miR-30d. Several targets including MAP4K4 and lims1 were further validated in tissue as well as in cultured CMs (n=4, p<0.05). miR-30d appears to be expressed in CMs, packaged into exosomes and micovesicles, and released in response to pathological rotational stress (n=2). Over-expression of miR-30d in CMs induces cellular hypertrophy with a unique expression signature of cardiac hypertrophy markers most consistent with physiological hypertrophy (n=3, p<0.05). Overexpression of miR-30d appears to be cardioprotective by abrogating TNF-induced increase in MAP4K4 expression (n=4, p<0.05). Conclusions: miR-30d is dynamically regulated in DHF and appears to play an important role in CM biology. Further insight into the role of ‘stretch’-regulated microRNAs such as miR-30d may pave the way for novel therapeutic and diagnostic strategies.

Functional role of miRNA in cardiac resynchronization therapy

2014 ◽  
Vol 15 (8) ◽  
pp. 1159-1168 ◽  
Author(s):  
Celestino Sardu ◽  
Raffaele Marfella ◽  
Gaetano Santulli ◽  
Giuseppe Paolisso
Keyword(s):  
Cardiac Resynchronization Therapy ◽  
Functional Role ◽  
Cardiac Resynchronization ◽  
Resynchronization Therapy

scholarly journals Valsartan Regulates PI3K/AKT Pathways through lncRNA GASL1 to Improve Isoproterenol-Induced Heart Failure

2022 ◽  
Vol 2022 ◽  
pp. 1-8
Author(s):  
Jian Zhou ◽  
Xiujuan Duan ◽  
Jibing Wang ◽  
Yunhong Feng ◽  
Jiangyong Yuan
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Akt Pathway ◽  
Chain Reaction ◽  
Qrt Pcr ◽  
Polymerase Chain ◽  
And Function ◽  
Rat Tail

Objective. This study is aimed at determining the expression and function of the GASL1 and PI3K/AKT pathways in isoproterenol- (ISO-) induced heart failure (HF). To determine the moderating effect of valsartan (VAL) on the progression of ISO-induced HF and to elucidate the related mechanism. Materials and Methods. First, in in vivo experiment, we examined the effect of VAL on cardiac function in rats with ISO-induced HF. Similarly, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of VAL on ISO-treated rat primary cardiomyocytes. Then, si-GASL1-transfected primary cardiomyocytes were constructed and Ad-si-GASL1 was injected through rat tail vein to achieve the effect of lowering GASL1 expression, so as to investigate the role of GASL1 in VAL’s treatment of ISO-induced HF. Results. In ISO-induced HF rat models, the GASL1 decreased while PI3K and p-AKT expressions were abnormally elevated and cardiac function deteriorated, and VAL was able to reverse these changes. In primary cardiomyocytes, ISO induces apoptosis of cardiomyocytes, and expression of GASL1 decreased while PI3K and p-AKT were abnormally elevated, which can be reversed by VAL. The transfection of primary cardiomyocytes with si-GASL1 confirmed that GASL1 affected the expression of PI3K, p-AKT, and the apoptosis of primary cardiomyocytes. Rat myocardium injected with Ad-si-GASL1 was found to aggravate the cardiac function improved by VAL. Conclusions. This study was the first to confirm that VAL improves ISO-induced HF by regulating the PI3K/AKT pathway through GASL1. And this study demonstrated a significant correlation between HF, VAL, GASL1, and the PI3K/AKT pathway.

scholarly journals HOTAIR contributes to the carcinogenesis of gastric cancer via modulating cellular and exosomal miRNAs level

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Jie Zhang ◽  
Wei-qing Qiu ◽  
Hongyi Zhu ◽  
Hua Liu ◽  
Jian-hua Sun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Noncoding Rna ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Capillary Formation ◽  
Qrt Pcr ◽  
Exosomal Mirnas ◽  
New Biomarkers

Abstract Gastric cancer (GC) is one of the most leading malignancies. Long noncoding RNA is related to GC. In this study, 11 miRNAs in the exosomes and six lncRNAs in the tissues was examined by qRT-PCR. Correlation analysis was used to analyze the relationship between miRNAs in exosome and lncRNAs in the tissues. Four miRNAs level in GC tissues were examined by qRT-PCR. MTT was used to determine cell viability. Flow cytometry was used to quantify the apoptotic cells. Transwell assay was used to examine the migration and invasion capacity. Dual-luciferase assay was used to examine the interaction between HOTAIR and miR-30a or -b. Capillary formation was used to determine the capillary formation capacity. Weak negative correlations were found between HOTAIR and miR-30a or -b in GC tissue samples. Interestingly, strong negative correlations were identified between the HOTAIR level in GC tissue samples and the miR-30a or -b levels in plasma exosomes. HOTAIR knockdown GC cells exhibited decreased migration, invasion, proliferation, and upregulated apoptosis, which released more miR-30a and -b into the exosomes. KRAS was upregulated when co-cultured with exosomes from HOTAIR overexpressed cells, and promoted GC cells proliferation, migration, and invasion. Meanwhile, HUVEC cells expressed increased VEGF-A and formatted more capillaries. Subsequently, we identified a 10mer target site of miR-30a or -b in HOTAIR sequence, and the overexpression of HOTAIR induced the degradation of miR-30a or -b, indicating a ceRNA role of HOTAIR. We report the negative correlation between the plasma miRNAs level and GC tissue HOTAIR expression for the first time and unveiled the ceRNA role of HOTAIR in GC. HOTAIR functions as an onco-lncRNA regulating the level of miR-30a and -b in both GC cells and exosomes. These findings may give insight into understanding the mechanism of GC pathogenesis and provide new biomarkers for clinical diagnosis.

Abstract 1878: Beneficial Electrophysiological Effects of bi-Ventricular Pacing for Cardiac Resynchronization Therapy in a Canine Model of Dyssynchronous Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takeshi Aiba ◽  
Andreas S Barth ◽  
Ting Liu ◽  
Khalid Chakir ◽  
Geoffrey G Hesketh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Resynchronization Therapy ◽  
Canine Model ◽  
Cardiac Resynchronization ◽  
Delayed Rectifier ◽  
Resynchronization Therapy ◽  
Beneficial Effects ◽  
Whole Cell Patch Clamp ◽  
Regional Gradient ◽  
Rv Pacing

Background : Cardiac resynchronization therapy (CRT) using bi-ventricular (bi-V) pacing improves cardiac function and mortality in patients with heart failure and dyssynchronous contraction (DHF). However, the mechanisms by which bi-V pacing restores DHF-induced electrophysiological remodeling remain controversial. We test the hypothesis that bi-V pacing has enhanced beneficial effects on DHF beyond resynchronization of contraction. Methods and Results : Adult dogs underwent RV pacing (190–200 bpm) for 6 weeks (DHF: n = 6), or 3-week DHF followed by 3 weeks of resynchronization by either bi-V pacing (n = 6) or RA pacing (A-pace: n = 5) at the same pacing rate. Myocytes were isolated from LV anterior (ANT) and lateral (LTR) walls in non-failing (NF), DHF, bi-V and A-pace dogs. Whole cell patch clamp was performed to measure action potential (AP), transient outward (I to ), inward rectifier (I K1 ) and delayed rectifier K + currents (I K ). L-type Ca 2+ current (I Ca,L ) and [Ca 2+ ] i transients (CaT) were measured in the absence (baseline) and presence of isoproterenol (ISO) (35°C). The QRS duration was wider in bi-V than in A-pace, the other ECG and hemodynamic parameters were not statistically different between Bi-V and A-pace dogs. Bi-V abbreviated DHF-induced prolongation of APD in the LTR but not ANT cells and diminished the regional gradient of APD, whereas A-pace less abbreviated APD in the LTR cells and still remained the gradient. Bi-V partially restored the DHF-induced down regulation of I K1 and I K but not I to , whereas A-pace restored only I K1 but not I K and I to . Furthermore, bi-V fully restored the DHF-induced reduction of I Ca,L at baseline and its ISO response, whereas A-pace did not restore I Ca,L at baseline but restored its ISO responsiveness. The CaT amplitude at baseline and in ISO were partially restored by both bi-V and A-pace but the restoration was more complete with bi-V compared to A-pace. Conclusion : Although both bi-V and A-pace resynchronize the LV contraction, DHF-induced downregulation of K + currents, Ca 2+ current and handling were less completely restored by A-pace compared with bi-V pace, suggesting bi-V pacing not only resynchronizes LV contraction but improves regional heterogeneity of repolarization and Ca 2+ homeostasis in DHF.

Insights from Novel Noninvasive CT and ECG Imaging Modalities on Electromechanical Myocardial Activation in a Canine Model of Ischemic Dyssynchronous Heart Failure

2016 ◽  
Vol 27 (12) ◽  
pp. 1454-1461 ◽  
Author(s):  
FADY DAWOUD ◽  
KARL H. SCHULERI ◽  
DAVID D. SPRAGG ◽  
B. MILAN HORÁČEK ◽  
RONALD D. BERGER ◽  
...  
Keyword(s):  
Heart Failure ◽  
Canine Model ◽  
Imaging Modalities ◽  
Dyssynchronous Heart Failure
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