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.

In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Krüppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.

Angiotensin II (angiotensin) and transforming growth factor (TGF)-beta(1) play an important role in cardiac fibrosis. We examined Smad proteins in 8-wk post-myocardial infarction (MI) rat hearts. AT(1) blockade (losartan) attenuated the activation of TGF-beta(1) in target tissues. Losartan administration (8 wk, 15 mg. kg(-1). day(-1)) normalized total Smad 2 overexpression in infarct scar and remnant heart tissue and normalized Smad 4 in infarct scar. Phosphorylated Smad 2 (P-Smad 2) staining decreased in cytosol from failing heart vs. the control, which was normalized by losartan, suggesting augmented P-Smad 2 movement into nuclei in untreated failing hearts. Using adult primary rat fibroblasts treated with angiotensin (10(-6) M), we noted rapid translocation (15 min) of P-Smad 2 into the nuclei from the cytosol. Nuclear P-Smad 2 protein level increased with angiotensin treatment, which was blocked by losartan. We conclude that angiotensin may influence total Smad 2 and 4 expression in post-MI heart failure and that angiotensin treatment is associated with rapid P-Smad 2 nuclear translocation in isolated fibroblasts. This study suggests that cross talk between angiotensin and Smad signaling is associated with fibrotic events in post-MI hearts.