Unknown,Transcriptomics,Genomics,Proteomics

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MiR-182 modulates myocardial hypertrophic response induced by angiogenesis in heart (miRNA)

ABSTRACT: Angiogenesis induced by placental growth factor (PlGF) in heart promotes myocardial hypertrophy through the paracrine action of endothelium-derived nitric oxide which triggers the degradation of RGS4 and subsequent activation of the Akt/mTORC1 pathway in cardiomyocytes. However, whether alterations in miRNAs contribute to the development of hypertrophy is largely undetermined. We found that miR-182 contributed to the hypertrophic response and activation of the Akt/mTORC1 pathway by suppressing the expression of Bcat2, Pink1, Adcy6, Foxo3. The expression of miRNAs and the effects of anti-miRs were investigated in the mouse model of myocardial angiogenesis induced by conditional, cardiac specific expression of PlGF. We also induced angiogenesis, but blocked hypertrophy by concomitant expression of PlGF and RGS4 (PlGF/RGS4 mice). Microarray profiling of miRNAs in LV myocardium was determined after 3 and 6 weeks of transgene expression.

ORGANISM(S): Mus musculus

SUBMITTER: Daniela Tirziu

PROVIDER: E-GEOD-67814 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have pro-migratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. Here, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with siRNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and NP-1, up-regulating the expression of anti-apoptotic molecules, pErk and Bcl2. Knock-down of PlGF transcripts reduced RA-FLS proliferation in a xeno-transplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. The FLSs were prepared from the synovial tissues of RA patients and incubated in DMEM supplemented with 10% FBS. Cells were cultured in RPMI supplemented with 10% FBS. There are 4 FLS samples treated with PlGF siRNA, and 4 FLS samples treated with control siRNA.

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MiR-182 modulates myocardial hypertrophic response induced by angiogenesis in heart (miRNA)

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