Dataset Information

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

ABSTRACT:

Background

Pitx2 (paired-like homeodomain 2 transcription factor) is crucial for heart development, but its role in heart failure (HF) remains uncertain. The present study lays the groundwork implicating Pitx2 signalling in different modalities of HF.

Methodology/principal findings

A variety of molecular, cell-based, biochemical, and immunochemical assays were used to evaluate: (1) Pitx2c expression in the porcine model of diastolic HF (DHF) and in patients with systolic HF (SHF) due to dilated and ischemic cardiomyopathy, and (2) molecular consequences of Pitx2c expression manipulation in cardiomyocytes in vitro. In pigs, the expression of Pitx2c, physiologically downregulated in the postnatal heart, is significantly re-activated in left ventricular (LV) failing myocardium which, in turn, is associated with increased expression of a restrictive set of Pitx2 target genes. Among these, Myf5 was identified as the top upregulated gene. In vitro, forced expression of Pitx2c in cardiomyocytes, but not in skeletal myoblasts, activates Myf5 in dose-dependent manner. In addition, we demonstrate that the level of Pitx2c is upregulated in the LV-myocardium of SHF patients.

Conclusions/significance

The results provide previously unrecognized evidence that Pitx2c is similarly reactivated in postnatal/adult heart at distinct HF phenotypes and suggest that Pitx2c is involved, directly or indirectly, in the regulation of Myf5 expression in cardiomyocytes.

SUBMITTER: Torrado M

PROVIDER: S-EPMC3942452 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

Torrado Mario M Franco Diego D Hernández-Torres Francisco F Crespo-Leiro María G MG Iglesias-Gil Carmen C Castro-Beiras Alfonso A Mikhailov Alexander T AT

PloS one 20140304 3

<h4>Background</h4>Pitx2 (paired-like homeodomain 2 transcription factor) is crucial for heart development, but its role in heart failure (HF) remains uncertain. The present study lays the groundwork implicating Pitx2 signalling in different modalities of HF.<h4>Methodology/principal findings</h4>A variety of molecular, cell-based, biochemical, and immunochemical assays were used to evaluate: (1) Pitx2c expression in the porcine model of diastolic HF (DHF) and in patients with systolic HF (SHF) ...[more]

PMID: 24595098

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Project description:BackgroundHeart failure leads to mitochondrial dysfunction and metabolic abnormalities of the failing myocardium coupled with an energy-depleted state and cardiac remodeling. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function through regulating the mitochondrial acetylome. It is interesting to note that unique cardiac and systemic microRNAs have been shown to play an important role in cardiac remodeling by modulating key signaling elements in the myocardium.MethodsCellular signaling was analyzed in human cardiomyocyte-like AC16 cells, and acetylation levels in rodent models of SIRT3-/-and transgenic microRNA-195 (miR-195) overexpression were compared with wild type. Luciferase assays, Western blotting, immunoprecipitation assays, and echocardiographic analysis were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured.ResultsIn failing human myocardium, we observed induction of miR-195 along with decreased expression of the mitochondrial deacetylase SIRT3 that was associated with increased global protein acetylation. We further investigated the role of miR-195 in SIRT3-mediated metabolic processes and its impact on regulating enzymes involved in deacetylation. Proteomic analysis of the total acetylome showed increased overall acetylation, and specific lysine acetylation of 2 central mitochondrial metabolic enzymes, PDH and ATP synthase, as well. miR-195 downregulates SIRT3 expression through direct 3'-untranslated region targeting. Treatments with either sirtuin inhibitor nicotinamide, small interfering RNA-mediated SIRT3 knockdown or miR-195 overexpression enhanced acetylation of PDH complex and ATP synthase. This effect diminished PDH and ATP synthase activity and impaired mitochondrial respiration.SIRT3-/- and miR-195 transgenic mice consistently showed enhanced global protein acetylation, including PDH complex and ATP synthase, associated with decreased enzymatic activity.ConclusionsAltogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Dataset Information

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

Background

Methodology/principal findings

Conclusions/significance

Publications

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

Similar Datasets

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