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

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.