Hypertrophy of cardiomyocytes is a common response to mechanical and hemodynamic stress and is characterized by an increase in cell size, protein synthesis, and re-expression of fetal genes. Left untreated, cardiac hypertrophy can ultimately lead to congestive heart failure - a leading cause of morbidity and mortality in our society. Studies over the past two decades have identified a number of signaling pathways and molecular mediators (e.g. GATA4) that promote the hypertrophic response. However, much less is known about the negative regulators of the process. Studies in this proposal investigate a novel molecular factor that inhibits cardiac hypertrophy termed KLF15. KLF15 is a member of the Kruppel-like family of transcription factors that are known to regulate key aspects of cellular development and function. KLF15 expression is low in the embryonic heart and induced in the postnatal period. Conversely, KLF15 expression is reduced by pressure-induced cardiac hypertrophy in vivo and by pro-hypertrophic agents in vitro. Consistent with these observations, KLF15 expression is reduced in human heart tissues from patients with aortic stenosis. Adenoviral overexpression of KLF15 in neonatal rat ventricular myocytes reduces basal and phenylephrine induced increases in cell size, protein synthesis, and gene expression. Multiple lines of evidence suggest that these effects are secondary to inhibition of the pro- hypertrophic factor GATA4. Finally, KLF15 null mice have been generated. Studies to date indicate that in response to pressure overload KLF15 null mice exhibit an eccentric form of pathologic remodeling. The goals of this proposal are: (1) To comprehensively study the effect of KLF15 on cardiac gene expression and function by gain and loss of function approaches;(2) To determine the molecular basis for KLF15's ability to inhibit myocyte hypertrophy in vitro;(3) To determine the functional consequences of altering KLF15 levels on GATA4 mediated hypertrophy in vivo. The results of these studies will provide insights regarding the role of KLF15 as an inhibitor of cardiac hypertrophy and may provide the foundation for novel therapeutic strategies in the treatment of heart failure.
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