Repression of cardiac hypertrophy by KLF15: underlying mechanisms and therapeutic implications

• Published in: PloS one 2012-05, Vol.7 (5), p.e36754
• Main Authors: Leenders, Joost J, Wijnen, Wino J, van der Made, Ingeborg, Hiller, Monika, Swinnen, Melissa, Vandendriessche, Thierry, Chuah, Marinee, Pinto, Yigal M, Creemers, Esther E
• Format: Article
• Language: English
• Subjects: Analysis; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animals; Binding Sites; Biological activity; Biology; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - therapy; Cardiomyocytes; Cell Differentiation; Cell survival; Clinical trials; COS Cells; Disease Models, Animal; DNA binding proteins; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fingers & toes; Gene expression; Gene Expression Regulation - drug effects; Gene therapy; Genetic Therapy; Health aspects; Heart; Heart diseases; Heart failure; Heart hypertrophy; Humans; Hypertrophy; Krueppel-like factor; Localization; Medicine; Mice; Mutant Proteins - metabolism; Myocyte enhancer factor 2; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Promoter Regions, Genetic; Proteins; Rodents; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Viruses; Zinc; Zinc finger proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036754

The Kruppel-like factor (KLF) family of transcription factors regulates diverse cell biological processes including proliferation, differentiation, survival and growth. Previous studies have shown that KLF15 inhibits cardiac hypertrophy by repressing the activity of pivotal cardiac transcription factors such as GATA4, MEF2 and myocardin. We set out this study to characterize the interaction of KLF15 with putative other transcription factors. We first show that KLF15 interacts with myocardin-related transcription factors (MRTFs) and strongly represses the transcriptional activity of MRTF-A and MRTF-B. Second, we identified a region within the C-terminal zinc fingers of KLF15 that contains the nuclear localization signal. Third, we investigated whether overexpression of KLF15 in the heart would have therapeutic potential. Using recombinant adeno-associated viruses (rAAV) we have overexpressed KLF15 specifically in the mouse heart and provide the first evidence that elevation of cardiac KLF15 levels prevents the development of cardiac hypertrophy in a model of Angiotensin II induced hypertrophy.