Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy
Sudeshna Fisch^*, Susan Gray^*, Stephane Heymans^†, Saptarsi M. Haldar^‡, Baiqiu Wang^‡, Otmar Pfister, Lei Cui, Ajay Kumar^*, Zhiyong Lin^‡, Sucharita Sen-Banerjee^*, Hiranmoy Das^‡, Christine A. Petersen, Ulrike Mende^*, Barbara A. Burleigh, Yan Zhu_, Yigal Pinto^†, Ronglih Liao, and Mukesh K. Jain^‡*
‡Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine
^*Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
^†Experimental and Molecular Cardiology/CARIM, University of Maastricht, Maastricht, The Netherlands; and _Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston
PNAS, April 24, 2007, vol. 104, No. 17

• > 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.
  
  NOTE: The B-Mode images in this paper and associated measurements were acquired using a Vevo 770 high-resolution micro-ultrasound system (VisualSonics, Toronto, Canada).