Kruppel-Like Factor 15 Is a Novel Regulator of Cardiomyocyte Hypertrophy.

Kruppel-like Factors (KLFs) in muscle biology

“…Our group identified KLF15 as being expressed in cardiomyocytes [40] and has recently provided evidence that this factor functions as a negative regulator of hypertrophic remodeling thus demonstrating a novel role for this family of transcription factors in postnatal cardiomyocyte function [27]. In addition, we have shown that KLF15 is also expressed in primary cardiac fibroblasts [27], however, the significance of this finding has not been completely elucidated. Figure 1A shows β-galactosidase staining of tissues from adult KLF15 (+/−) mice (in which a nuclear localized lacZ gene was "knocked in" to the KLF15 locus by homologous recombination) and clearly illustrates robust KLF15 expression in all three muscle types.…”

“…Furthermore, KLF15 expression is dramatically reduced with pressure overload hypertrophy in murine models as well as in human subjects with valvular aortic stenosis. [27,40] KLF15 expression is also reduced by pharmacologic agonists known to induce cardiomyocyte hypertrophy such as phenylephrine and endothelin-1 [27]. Finally, a recent report detailing expression profiles in cultured myocytes treated with hydrogen-peroxide to induce oxidative stress revealed over 50% reduction in KLF15 expression [41] although the physiologic relevance of this finding is not known.…”

“…To date, there are four published reports describing the function of KLFs in the heart -KLF5 in cardiac fibroblasts [28], KLF15 (postnatal) [27] and KLF13 (embryonic) [37] in cardiomyocytes, and a brief report describing a cardiac phenotype in systemic KLF10-null mice [38]. Figure 1 highlights some of these published findings pertaining to KLFs in the myocardium.…”

“…To understand the role of KLF15 in cardiac biology, we undertook gain and loss of function studies [27]. Overexpression of KLF15 in neonatal rat ventricular myocytes potently inhibits three cardinal features of hypertrophic remodeling (cell growth, protein synthesis and hypertrophic gene expression) under both basal and stimulated conditions.…”

“…From a mechanistic standpoint, KLF15 can potently inhibit the transcriptional activity of MEF2 and GATA4 [27] -two well-characterized transcriptional activators of hypertrophic remodeling that can function synergistically in the myocardium [42,43]. The primary downstream mechanism by which MEF2 and GATA4 carry out their pro-hypertrophic effects is via enhanced DNA binding.…”