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miR-185 plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways.

Kim JO, Song DW, Kwon EJ, Hong SE, Song HK, Min CK, Kim do H - PLoS ONE (2015)

Bottom Line: The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart.The expression of phospho-phospholamban (Thr-17), a marker of CaMKIIδ activity, was also significantly reduced by miR-185.In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.

ABSTRACT
MicroRNA (miRNA) is an endogenous non-coding RNA species that either inhibits RNA translation or promotes degradation of target mRNAs. miRNAs often regulate cellular signaling by targeting multiple genes within the pathways. In the present study, using Gene Set Analysis, a useful bioinformatics tool to identify miRNAs with multiple target genes in the same pathways, we identified miR-185 as a key candidate regulator of cardiac hypertrophy. Using a mouse model, we found that miR-185 was significantly down-regulated in myocardial cells during cardiac hypertrophy induced by transverse aortic constriction. To confirm that miR-185 is an anti-hypertrophic miRNA, genetic manipulation studies such as overexpression and knock-down of miR-185 in neonatal rat ventricular myocytes were conducted. The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart. Our study further identified Camk2d, Ncx1, and Nfatc3 as direct targets of miR-185. The activity of Nuclear Factor of Activated T-cell (NFAT) and calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ) was negatively regulated by miR-185 as assessed by NFAT-luciferase activity and western blotting. The expression of phospho-phospholamban (Thr-17), a marker of CaMKIIδ activity, was also significantly reduced by miR-185. In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

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Working model illustrating the multiple targets of miR-185 in the calcium-dependent cardiac hypertrophy signaling pathway.
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pone.0122509.g006: Working model illustrating the multiple targets of miR-185 in the calcium-dependent cardiac hypertrophy signaling pathway.

Mentions: Cardiac hypertrophy is a complex gene regulatory disorder that involves aberrant expression of coding mRNAs and regulatory non-coding RNAs. Among the noncoding RNAs, miRNA is the most widely studied one. It is now generally accepted that miRNAs often regulate multiple transcripts in the same biological processes [8]. However, the traditional approach has mostly focused on the identification of a single target for the specific miRNAs in different tissues. In the present study, we used cardiac tissue specific GSA to identify the critical miRNAs and their multiple targets involved in cardiac hypertrophy. Among the 18 GSA-identified cardiac hypertrophy-associated miRNAs, we selected miR-185 for further studies. We found that miR-185 plays an important anti-hypertrophic role in the heart and it has three major targets involved in the hypertrophic processes such as Ncx1, Nfatc3, and Camk2d (Fig. 6).


miR-185 plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways.

Kim JO, Song DW, Kwon EJ, Hong SE, Song HK, Min CK, Kim do H - PLoS ONE (2015)

Working model illustrating the multiple targets of miR-185 in the calcium-dependent cardiac hypertrophy signaling pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358957&req=5

pone.0122509.g006: Working model illustrating the multiple targets of miR-185 in the calcium-dependent cardiac hypertrophy signaling pathway.
Mentions: Cardiac hypertrophy is a complex gene regulatory disorder that involves aberrant expression of coding mRNAs and regulatory non-coding RNAs. Among the noncoding RNAs, miRNA is the most widely studied one. It is now generally accepted that miRNAs often regulate multiple transcripts in the same biological processes [8]. However, the traditional approach has mostly focused on the identification of a single target for the specific miRNAs in different tissues. In the present study, we used cardiac tissue specific GSA to identify the critical miRNAs and their multiple targets involved in cardiac hypertrophy. Among the 18 GSA-identified cardiac hypertrophy-associated miRNAs, we selected miR-185 for further studies. We found that miR-185 plays an important anti-hypertrophic role in the heart and it has three major targets involved in the hypertrophic processes such as Ncx1, Nfatc3, and Camk2d (Fig. 6).

Bottom Line: The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart.The expression of phospho-phospholamban (Thr-17), a marker of CaMKIIδ activity, was also significantly reduced by miR-185.In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.

ABSTRACT
MicroRNA (miRNA) is an endogenous non-coding RNA species that either inhibits RNA translation or promotes degradation of target mRNAs. miRNAs often regulate cellular signaling by targeting multiple genes within the pathways. In the present study, using Gene Set Analysis, a useful bioinformatics tool to identify miRNAs with multiple target genes in the same pathways, we identified miR-185 as a key candidate regulator of cardiac hypertrophy. Using a mouse model, we found that miR-185 was significantly down-regulated in myocardial cells during cardiac hypertrophy induced by transverse aortic constriction. To confirm that miR-185 is an anti-hypertrophic miRNA, genetic manipulation studies such as overexpression and knock-down of miR-185 in neonatal rat ventricular myocytes were conducted. The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart. Our study further identified Camk2d, Ncx1, and Nfatc3 as direct targets of miR-185. The activity of Nuclear Factor of Activated T-cell (NFAT) and calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ) was negatively regulated by miR-185 as assessed by NFAT-luciferase activity and western blotting. The expression of phospho-phospholamban (Thr-17), a marker of CaMKIIδ activity, was also significantly reduced by miR-185. In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

Show MeSH
Related in: MedlinePlus