The Mef2 Transcription Network Is Disrupted in Myotonic Dystrophy Heart Tissue, Dramatically Altering miRNA and mRNA Expression

SUMMARYMyotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of DM1-related deaths. Despite these figures, the mechanisms underlying cardiac-based DM1 phenotypes are unknown. Herein, we report that upregulation of a non-muscle splice isoform of RNA binding protein RBFOX2 in DM1 heart tissue—due to altered splicing factor and microRNA activities—induces cardiac conduction defects in DM1 individuals. Mice engineered to express the non-muscle RBFOX2 isoform in heart via tetracycline-inducible transgenesis, or CRISPR/Cas9-mediated genome editing, reproduced DM1-related cardiac-conduction delay and spontaneous episodes of arrhythmia. Further, by integrating RNA binding with cardiac transcriptome datasets from both DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX2-driven splicing defects in the voltage-gated sodium and potassium channels, which can alter their electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis.

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Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue

Physiological Genomics ◽

10.1152/physiolgenomics.00074.2010 ◽

2011 ◽

Vol 43 (10) ◽

pp. 581-594 ◽

Cited By ~ 21

Author(s):

Jane Synnergren ◽

Caroline Améen ◽

Anders Lindahl ◽

Björn Olsson ◽

Peter Sartipy

Keyword(s):

Stem Cell ◽

Mrna Expression ◽

Mirna Expression ◽

Target Genes ◽

Cardiac Tissue ◽

Heart Tissue ◽

Mrna Levels ◽

Regulatory Pathways ◽

Adult Heart ◽

Starting Point

Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.

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Improving insulin sensitivity via activation of PPAR-γ increases telomerase activity in the heart of OLETF rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00421.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. H2188-H2195 ◽

Cited By ~ 33

Author(s):

Naoki Makino ◽

Toyoki Maeda ◽

Jun-ichi Oyama ◽

Yosihiro Higuchi ◽

Koji Mimori

Keyword(s):

Insulin Sensitivity ◽

Mrna Expression ◽

Telomerase Activity ◽

Heart Tissue ◽

Diabetic Animal ◽

Model Assessment ◽

Telomere Repeat ◽

Oletf Rats ◽

Long Evans ◽

Telomere Biology

This study was conducted to examine telomere biology in terms of improving insulin sensitivity in a type 2 diabetic animal model: Otsuka Long-Evans Tokushima fatty (OLETF) rats. To improve insulin sensitivity, pioglitazone (PG; 10 mg·kg−1·day−1) was administrated to OLETF rats from 20 to 40 wk of age, and the effects of treatment were compared with those in untreated OLETF or control Long-Evans Tokushima Otsuka fatty rats. At the end of the study, the homeostasis model assessment of insulin resistance significantly increased in OLETF rats but decreased in OLETF rats treated with PG. No shortening of telomere length was observed in the heart tissue of OLETF rats, whereas telomerase activity was decreased in OLETF heart tissue. The mRNA expression of both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. The protein expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase was reduced in OLETF rats. On the other hand, myocardial matrix metalloproteinase-9 expression was elevated in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. However, protein and mRNA expression of Sirt1, a lifespan modulator, were attenuated in OLETF rat hearts, although they were enhanced in OLETF rats with PG treatement. Myocardial fibrosis was less extensive and diastolic dysfunction more greatly ameliorated in PG-treated OLETF rats than in OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisom proliferator-activated receptor-γ may exert regulatory effects on cardiac telomere biology and may have desirable morphological and functional effects on the diabetic heart.

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EFFECTS OF NANOCURCUMIN IN RATS WITH DIABETES INDUCED WITH STREPTOZOTOCIN AND NICOTINAMIDE: MRNA EXPRESSION OF B-TYPE NATRIURETIC PEPTIDE

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018.v10s1.38 ◽

2018 ◽

Vol 10 (1) ◽

pp. 175

Author(s):

Maryam Ulfa ◽

Dyah Suci Handayani ◽

Hotlina Nainggolan ◽

Wawaimuli Arozal

Keyword(s):

Polymerase Chain Reaction ◽

Mrna Expression ◽

Natriuretic Peptide ◽

Diabetic Cardiomyopathy ◽

Heart Tissue ◽

Diabetic Rats ◽

Chain Reaction ◽

Polymerase Chain ◽

Type 2 Diabetic

Objective: This study aimed to determine the effects of nanocurcumin on cardiomyopathy, assessed by the expression of B-type natriuretic peptide(BNP) mRNA in heart tissue.Methods: Type 2 diabetic rats were induced with streptozotocin and nicotinamide. Nanocurcumin was orally administered (100 mg/kg/day)for 30 days. BNP-45 mRNA expression in the heart tissue was measured using quantitative reverse transcription-polymerase chain reaction andcalculated using the Livak method.Results: BNP-45 levels increased significantly (p<0.05) in diabetic rats compared with the normal group. Nanocurcumin treatment at a dose of100 mg/kg for 30 days significantly decreased BNP-45 expression levels (p<0.05) compared with diabetic rats without treatment.Conclusion: Nanocurcumin may be beneficial in inhibiting the progression of diabetic cardiomyopathy by suppressing the expression of BNP-45.

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