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Role of micro-RNAs in pathophysiology of diabetic cardiomyopathy.

ABSTRACT: Diabetic cardiomyopathy (DCM), occurs independent of Hypertension, Coronary artery disease, or any other known cardiac disease and is characterized by myocardial fibrosis, myocytes loss and hypertrophy. The molecular mechanisms leading to these diseased cardiac phenotype are still being elucidated. A small number of studies have demonstrated that altered expression of several microRNAs are associated with ischemia , mechanical overload, or cardiovascular biology; however, much work is still required to identify individual or group of microRNAs and their role in the pathophysiology of diabetic cardiomyopathy. The aim of present study was to identify the expression of individual or group of microRNAs associated with myocytes hypertrophy and myocardial fibrosis during DCM. MicroRNAs expression profiles were studied in myocardium from High Fat diet and streptozotocin (STZ) induced diabetic (n=4) and non-diabetic (n=2) Wistar rats. All normalized and filtered microRNAs (n=780) processed for differential expression study using unpaired T-test in Gene spring in which unpaired comparison has been performed as test vs. control. After unpaired T-test, total 72 microRNAs were found to be significantly expressed with P-value ≤0.05. Differentially expression analysis was performed and at fold Change cut off ≥ 1.0, all 780 microRNA passed and 39 out of 780 microRNAs were differentially expressed on fold Change cut-off ≥1.5. These results indicate that during the development and progression of DCM, various microRNAs were differentially expressed and may participate in the regulation of various signaling pathways leading to myocytes hypertrophy, apoptosis and cardiac fibrosis.

ORGANISM(S): synthetic construct Rattus norvegicus

PROVIDER: GSE44179 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA188974

REPOSITORIES: GEO

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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Role of micro-RNAs in pathophysiology of diabetic cardiomyopathy.

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