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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.

Pitx2c Is Reactivated in the Failing Myocardium and Stimulates Myf5 Expression in Cultured Cardiomyocytes