YY1 is a transcription factor that can repress or activate the transcription of a variety of genes. Here, we show that the function of YY1 as a repressor in cardiac myocytes is tightly dependent on its ability to interact with histone deacetylase 5 (HDAC5). YY1 interacts with HDAC5, and overexpression of YY1 prevents HDAC5 nuclear export in response to hypertrophic stimuli and the increase in cell size and re-expression of fetal genes that accompany pathological cardiac hypertrophy. Knockdown of YY1 results in up-regulation of all genes present during fetal development and increases the cell size of neonatal cardiac myocytes. Moreover, overexpression of a YY1 deletion construct that does not interact with HDAC5 results in transcription activation, suggesting that HDAC5 is necessary for YY1 function as a transcription repressor. In support of this relationship, we show that knockdown of HDAC5 results in transcription activation by YY1. Finally, we show that YY1 interaction with HDAC5 is dependent on the HDAC5 phosphorylation domain and that overexpression of YY1 reduces HDAC5 phosphorylation in response to hypertrophic stimuli. Our results strongly suggest that YY1 functions as an antihypertrophic factor by preventing HDAC5 nuclear export and that up-regulation of YY1 in human heart failure may be a protective mechanism against pathological hypertrophy.

Introduction Chronic activation of the β1-adrenergic receptor (β1-AR) signaling can have deleterious effects on the heart, and animal models over-expressing β1-ARs develop a dilated cardiomyopathy and heart failure. In the classical β-AR pathway, receptor occupancy by an agonist results in increased cyclic AMP (cAMP) levels and activation of protein kinase A (PKA). However, the role of PKA dependent signaling in the development and progression of cardiomyopathies and heart failure is controversial because β-AR signal transduction is generally desensitized in the failing heart, and PKA activity is not increased. Methods and Results Neonatal Rat Ventricular Myocytes (NRVMs) were acutely (15 minutes) or chronically (48 hours) treated with isoproterenol, and phosphorylation of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) was measured. Acute β1-AR stimulation or expression of constitutively active (CA)-PKA reduced α1-adrenergic-mediated phosphorylation of HDAC5 and PKD by activation of a phosphatase. Over-expression of CA-PKA also reduced α1-adrenergic-mediated increased expression of contractile protein fetal isoforms and promoted repression of adult isoforms, but had no effect on α1-adrenergic-mediated cellular hypertrophy. Conclusions These data indicate that the PKA dependent arm of β-AR signaling can be anti-hypertrophic and presumably beneficial, through dephosphorylation of PKD and HDAC5 and reduction of hypertrophic fetal isoform gene expression.

The natural history of allergic diseases suggests bidirectional and progressive relationships between allergic disorders of the skin, lung and gut indicative of mucosal organ cross-talk. However, impacts of local allergic inflammation on the cellular landscape of remote mucosal organs along the skin:lung:gut axis are not yet known. Eosinophils are tissue-dwelling innate immune leukocytes associated with allergic diseases. Emerging data suggest heterogeneous phenotypes of tissue-dwelling eosinophils contribute to multifaceted roles that favor homeostasis or disease. This study investigated the impact of acute local allergen exposure on the frequency and phenotype of tissue eosinophils within remote mucosal organs. Our findings demonstrate allergen challenge to skin, lung or gut elicited not only local eosinophilic inflammation, but also increased the number and frequency of eosinophils within remote, allergen non -exposed lung and intestine. Remote allergen-elicited lung eosinophils exhibited an inflammatory phenotype and their presence associated with enhanced susceptibility to airway inflammation induced upon subsequent inhalation of a different allergen. These data demonstrate, for the first time, a direct effect of acute allergic inflammation on the phenotype and frequency of tissue eosinophils within antigen non-exposed remote mucosal tissues associated with remote organ priming for allergic inflammation.

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