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Thyroid Hormone-Regulated Cardiac microRNAs are Predicted to Suppress Pathological Hypertrophic Signaling.

Janssen R, Zuidwijk MJ, Kuster DW, Muller A, Simonides WS - Front Endocrinol (Lausanne) (2014)

Bottom Line: A total of 52 T3-regulated miRNAs showing a >2-fold change (p < 0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy.A total of 27 mRNAs were identified as bona fide targets.Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, VU University Medical Center, Institute for Cardiovascular Research , Amsterdam , Netherlands.

ABSTRACT
Cardiomyocyte size in the healthy heart is in part determined by the level of circulating thyroid hormone (TH). Higher levels of TH induce ventricular hypertrophy, primarily in response to an increase in hemodynamic load. Normal cardiac function is maintained in this form of hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy. MicroRNAs (miRNAs) are important modulators of signal-transduction pathways driving adverse remodeling. Because little is known about the involvement of miRNAs in cardiac TH action and hypertrophy, we examined the miRNA expression profile of the hypertrophied left ventricle (LV) using a mouse model of TH-induced cardiac hypertrophy. C57Bl/6J mice were rendered hypothyroid by treatment with propylthiouracil and were subsequently treated for 3 days with TH (T3) or saline. T3 treatment increased LV weight by 38% (p < 0.05). RNA was isolated from the LV and expression of 641 mouse miRNAs was determined using Taqman Megaplex arrays. Data were analyzed using RQ-manager and DataAssist. A total of 52 T3-regulated miRNAs showing a >2-fold change (p < 0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy. The analysis was further restricted to proteins that have been validated as key factors in hypertrophic signal transduction in mouse models of ventricular remodeling. A total of 27 mRNAs were identified as bona fide targets. The predicted regulation of 19% of these targets indicates enhancement of physiological hypertrophy, while 56% indicates suppression of pathological remodeling. Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling. This may be relevant for our understanding of the progression of adverse remodeling, since cardiac TH levels are known to decrease substantially in various forms of pathological hypertrophy.

No MeSH data available.


Related in: MedlinePlus

Clustering of target mRNAs into biological groups. Clustering of predicted target mRNAs into biological groups was performed with IPA. Predicted target mRNAs were represented in processes involved in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism.” Numbers indicate the number of target mRNAs involved in the corresponding process.
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Figure 3: Clustering of target mRNAs into biological groups. Clustering of predicted target mRNAs into biological groups was performed with IPA. Predicted target mRNAs were represented in processes involved in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism.” Numbers indicate the number of target mRNAs involved in the corresponding process.

Mentions: Of the total of 149 differentially regulated miRNAs, 52 met the criteria of at least a twofold increase or a 50% decrease and having a p-value < 0.05. This group of 52 forms a unique signature of miRNAs differentially regulated after 3 days of T3 treatment (Figure 2). To test for potential target mRNAs, in silico target prediction was performed using a web-based entry tool, IPA. Thirty-one out of the 52 miRNAs had targeting information available in the Ingenuity database and could be used in the IPA analysis (Table S2 in Supplementary Material). The predicted interaction between miRNA and its target mRNA was based on sequence homology of the miRNA seed region and the target sequence present in the 3′ UTR of the mRNA. The analysis was furthermore restricted to mRNAs known to be expressed in heart tissue. In this way, a total of 3274 mRNAs were identified as potential targets of the group of 31 miRNAs. An IPA “core” analysis was subsequently performed to relate the predicted target mRNAs to known biological functions and processes. This revealed that the predicted target mRNAs were significantly represented in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism” (Figure 3).


Thyroid Hormone-Regulated Cardiac microRNAs are Predicted to Suppress Pathological Hypertrophic Signaling.

Janssen R, Zuidwijk MJ, Kuster DW, Muller A, Simonides WS - Front Endocrinol (Lausanne) (2014)

Clustering of target mRNAs into biological groups. Clustering of predicted target mRNAs into biological groups was performed with IPA. Predicted target mRNAs were represented in processes involved in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism.” Numbers indicate the number of target mRNAs involved in the corresponding process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202793&req=5

Figure 3: Clustering of target mRNAs into biological groups. Clustering of predicted target mRNAs into biological groups was performed with IPA. Predicted target mRNAs were represented in processes involved in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism.” Numbers indicate the number of target mRNAs involved in the corresponding process.
Mentions: Of the total of 149 differentially regulated miRNAs, 52 met the criteria of at least a twofold increase or a 50% decrease and having a p-value < 0.05. This group of 52 forms a unique signature of miRNAs differentially regulated after 3 days of T3 treatment (Figure 2). To test for potential target mRNAs, in silico target prediction was performed using a web-based entry tool, IPA. Thirty-one out of the 52 miRNAs had targeting information available in the Ingenuity database and could be used in the IPA analysis (Table S2 in Supplementary Material). The predicted interaction between miRNA and its target mRNA was based on sequence homology of the miRNA seed region and the target sequence present in the 3′ UTR of the mRNA. The analysis was furthermore restricted to mRNAs known to be expressed in heart tissue. In this way, a total of 3274 mRNAs were identified as potential targets of the group of 31 miRNAs. An IPA “core” analysis was subsequently performed to relate the predicted target mRNAs to known biological functions and processes. This revealed that the predicted target mRNAs were significantly represented in “cardiovascular system development and function,” “cell death and survival,” “cellular growth and proliferation,” “energy metabolism,” and “lipid metabolism” (Figure 3).

Bottom Line: A total of 52 T3-regulated miRNAs showing a >2-fold change (p < 0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy.A total of 27 mRNAs were identified as bona fide targets.Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, VU University Medical Center, Institute for Cardiovascular Research , Amsterdam , Netherlands.

ABSTRACT
Cardiomyocyte size in the healthy heart is in part determined by the level of circulating thyroid hormone (TH). Higher levels of TH induce ventricular hypertrophy, primarily in response to an increase in hemodynamic load. Normal cardiac function is maintained in this form of hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy. MicroRNAs (miRNAs) are important modulators of signal-transduction pathways driving adverse remodeling. Because little is known about the involvement of miRNAs in cardiac TH action and hypertrophy, we examined the miRNA expression profile of the hypertrophied left ventricle (LV) using a mouse model of TH-induced cardiac hypertrophy. C57Bl/6J mice were rendered hypothyroid by treatment with propylthiouracil and were subsequently treated for 3 days with TH (T3) or saline. T3 treatment increased LV weight by 38% (p < 0.05). RNA was isolated from the LV and expression of 641 mouse miRNAs was determined using Taqman Megaplex arrays. Data were analyzed using RQ-manager and DataAssist. A total of 52 T3-regulated miRNAs showing a >2-fold change (p < 0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy. The analysis was further restricted to proteins that have been validated as key factors in hypertrophic signal transduction in mouse models of ventricular remodeling. A total of 27 mRNAs were identified as bona fide targets. The predicted regulation of 19% of these targets indicates enhancement of physiological hypertrophy, while 56% indicates suppression of pathological remodeling. Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling. This may be relevant for our understanding of the progression of adverse remodeling, since cardiac TH levels are known to decrease substantially in various forms of pathological hypertrophy.

No MeSH data available.


Related in: MedlinePlus