Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Abstract

Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…1C). Conversely, KLF15 has been shown to be substantially down-regulated in rodent models of heart failure (20,21), a pathologic state where myocardial lipid utilization is reduced (5,6). Consistent with this rodent data, we found KLF15 to be significantly reduced in failing human hearts with a significant recovery of expression after mechanical unloading with a left ventricular assist device (Fig.…”

“…Plasmids and Adenoviruses-Expression plasmids containing the mouse KLF15 cDNA have been described previously (20). The Ϫ1.2 kb promoter region of mouse Slc27a1 (Fatp1) was PCR-amplified from purified genomic DNA (Promega) and subcloned into pGL3-basic (Promega).…”

“…Cell Culture-Neonatal rat ventricular myocytes (NRVM) were isolated from 2-day-old rat pups and isolated and maintained under standard conditions as described previously (20,21,27). Isolated NRVM were cultured for 24 -48 h under quiescent conditions by the inclusion of serum-free DMEM supplemented with insulin, transferrin, and selenium prior to experiments.…”

“…Promoter-Luciferase Studies-Transient transfections of the indicated promoter plasmids using cultured NRVM or C2C12 cells at 70% confluence were carried out using Fugene6 (Roche Applied Science and Promega) following the manufacturer's instructions, and bioluminescence was recorded on a Veritas luminometer (Turner Biosystems) as described previously (20,26).…”

Time course of gene expression during mouse skeletal muscle hypertrophy

“…The inactivation of Klf15 resulted in a modest but significant increase in lean mass that was associated with a reduced expression of multiple genes encoding amino acid-degrading enzymes, including Bcat2 (8). However, a more recent study from this same group reported no change in skeletal muscle mass (9), while Klf15 null mice developed a severe cardiac hypertrophy in response to pressure overload (6). Alternatively, Klf15 overexpression was shown to accelerate catabolism of BCAA, resulting in myotube and skeletal muscle atrophy (28).…”