Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 17, Pages 7074-7079Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701981104
Keywords
heart; transcription
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Funding
- NHLBI NIH HHS [F32 HL 78183, R01 HL072952, HL 72952, F32 HL077052, P01 HL048743, HL 76754, R01 HL076754, R01 HL075427, F32 HL 077052, P01 HL 48743, HL 75427, F32 HL078183] Funding Source: Medline
- NIDDK NIH HHS [DK 064950, K01 DK064950] Funding Source: Medline
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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 nnyocyte 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.
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