Abstract 898: The Kruppel-Like Factor KLF15 is a Novel Regulator of Cardiomyocyte Hypertrophy
Background: Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. The molecular mechanisms underlying this disease process remain incompletely understood. Herein, we identify the Kruppel-like factor 15 (KLF15) as a novel inhibitor of cardiac hypertrophy.
Methods and Results: KLF15 expression is robust in the adult rat heart and reduced in rodent models of hypertrophy as shown both in vivo by performing trans-aortic constriction (AAC) on adult rats and in vitro upon treatment of neonatal rat ventricular myocytes (NRVM) with prohypertrophic stimuli, phenylephrine (PE) and endothelin-1 (ET-1). Consistent with these observations in rodents, KLF15 protein is reduced in the myocardium of human subjects with chronic aortic-stenosis when compared to control patients undergoing CABG. Furthermore, sustained expression of KLF15 potently inhibits the ability of pro-hypertrophic agonists such as PE to induce classic features of cardiomyocyte hypertrophy including increased fetal gene expression (e.g.ANF/BNP), cell size, and protein synthetic capacity. To assess the role of this factor in vivo, the KLF15 gene was targeted by homologous recombination. KLF15-null mice are viable but in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight and hypertrophic gene expression, marked cavity dilatation, increased myocyte size and reduced left ventricular systolic function. Furthermore, our studies provide evidence that KLF15 can affect hypertrophy, at least in part, through its inhibitory effects on the prohypertrophic transcriptional regulator GATA4. Mechanistically, a combination of promoter analyses, gel-shift/ chromatin immunoprecipitation assays and GST pull-down studies suggest that KLF15 can inhibit GATA4 binding and transcriptional activity on the ANF/BNP promoters.
Conclusion: These observations identify KLF15 as part of a heretofore-unrecognized transcriptional pathway regulating the cardiac response to hemodynamic stress.