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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

Predicted target mRNAs involved in signature pathways of cardiac hypertrophy. Of the 2312 mRNAs that were targeted by either up- or downregulated miRNAs, 27 bona fide targets were found to be involved in cardiac hypertrophy. The presented molecules are members of at least one of the eight selected signature transduction pathways involved in the development of cardiac hypertrophy. Red, the corresponding miRNA was shown to be downregulated in HOT3, which resulted in a predicted upregulation of its target mRNA; green, the corresponding miRNA was shown to be upregulated in hyperthyroid LV, which resulted in a predicted downregulation of its target mRNA. “*” Indicates target mRNAs involved in physiological hypertrophy.
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Figure 4: Predicted target mRNAs involved in signature pathways of cardiac hypertrophy. Of the 2312 mRNAs that were targeted by either up- or downregulated miRNAs, 27 bona fide targets were found to be involved in cardiac hypertrophy. The presented molecules are members of at least one of the eight selected signature transduction pathways involved in the development of cardiac hypertrophy. Red, the corresponding miRNA was shown to be downregulated in HOT3, which resulted in a predicted upregulation of its target mRNA; green, the corresponding miRNA was shown to be upregulated in hyperthyroid LV, which resulted in a predicted downregulation of its target mRNA. “*” Indicates target mRNAs involved in physiological hypertrophy.

Mentions: We next focused our analyses on target mRNAs encoding proteins which have been shown to be critical components of hypertrophic signaling pathways, i.e., the IGF-1-, NFAT-, Ca2+-, GPCR-, JAK/STAT-, PI3K/Akt-, ERK/MAPK-, and TH-signaling pathways (16) and which have been validated in mouse models of pathological and/or physiological hypertrophy. Analysis was furthermore limited to mRNAs that are solely targeted by either up- or downregulated miRNAs, so that the effect of miRNA regulation on the expression of these signaling components is unequivocal. This approach resulted in 27 candidates (Figure 4). In depth analyses using IPA and additional literature searches revealed that the predicted regulation of 5 of these targets (19%) results in enhancement of physiological hypertrophy, whereas regulation of 15 of these targets (56%) results in suppression of pathological remodeling (Table 2).


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)

Predicted target mRNAs involved in signature pathways of cardiac hypertrophy. Of the 2312 mRNAs that were targeted by either up- or downregulated miRNAs, 27 bona fide targets were found to be involved in cardiac hypertrophy. The presented molecules are members of at least one of the eight selected signature transduction pathways involved in the development of cardiac hypertrophy. Red, the corresponding miRNA was shown to be downregulated in HOT3, which resulted in a predicted upregulation of its target mRNA; green, the corresponding miRNA was shown to be upregulated in hyperthyroid LV, which resulted in a predicted downregulation of its target mRNA. “*” Indicates target mRNAs involved in physiological hypertrophy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Predicted target mRNAs involved in signature pathways of cardiac hypertrophy. Of the 2312 mRNAs that were targeted by either up- or downregulated miRNAs, 27 bona fide targets were found to be involved in cardiac hypertrophy. The presented molecules are members of at least one of the eight selected signature transduction pathways involved in the development of cardiac hypertrophy. Red, the corresponding miRNA was shown to be downregulated in HOT3, which resulted in a predicted upregulation of its target mRNA; green, the corresponding miRNA was shown to be upregulated in hyperthyroid LV, which resulted in a predicted downregulation of its target mRNA. “*” Indicates target mRNAs involved in physiological hypertrophy.
Mentions: We next focused our analyses on target mRNAs encoding proteins which have been shown to be critical components of hypertrophic signaling pathways, i.e., the IGF-1-, NFAT-, Ca2+-, GPCR-, JAK/STAT-, PI3K/Akt-, ERK/MAPK-, and TH-signaling pathways (16) and which have been validated in mouse models of pathological and/or physiological hypertrophy. Analysis was furthermore limited to mRNAs that are solely targeted by either up- or downregulated miRNAs, so that the effect of miRNA regulation on the expression of these signaling components is unequivocal. This approach resulted in 27 candidates (Figure 4). In depth analyses using IPA and additional literature searches revealed that the predicted regulation of 5 of these targets (19%) results in enhancement of physiological hypertrophy, whereas regulation of 15 of these targets (56%) results in suppression of pathological remodeling (Table 2).

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