Cardiomyocyte hypertrophy is characterized by an increase in protein synthesis and reactivation of fetal genes. Although hypertrophy is initially compensatory for an increased workload, prolongation of this process is maladaptive and can lead to heart failure, arrhythmia, and sudden death. Kruppel-like factors are a class of DNA-binding transcription factors which regulate cellular differentiation and tissue development. KLF15, recently identified in our laboratory, is highly expressed in ventricular cardiac myocytes. Its expression in cardiomyocytes is induced postnatally and is markedly attenuated in cardiac hypertrophy following trans-aortic banding. Adenoviral overexpression of KLF15 in neonatal rat ventricular myocytes potently inhibits the expression of ANP/BNP, and induces that of GLUT4. Consistent with these observations, KLF15 inhibits ANF/BNP and induces GLUT4 promoter activity. Our studies support the presence of both activation and repression domains within the non-DNA binding region of KLF15. Finally, to understand the role of KFL15 in vivo, KLF15 null mice have been generated. We hypothesize that KLF15 may function as a negative regulator of cardiac hypertrophy. The studies in this proposal will explore the mechanistic basis for KLF15's ability to regulate gene expression and the effect of KLF15 deficiency on cardiac gene expression, function, and response to experimental hypertrophy. These studies will provide insight into the role of KLF15 in cardiomyocyte biology and may serve as the basis for novel strategies to regulate cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL077052-02
Application #
6899738
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Meadows, Tawanna
Project Start
2004-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$51,548
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Gray, Susan; Wang, Baiqiu; Orihuela, Yvette et al. (2007) Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab 5:305-12
Fisch, Sudeshna; Gray, Susan; Heymans, Stephane et al. (2007) Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 104:7074-9