title: Repression of cardiac hypertrophy by KLF15: underlying mechanisms and therapeutic implications.
abstract: 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.
authors.affiliation: Heart Failure Research Center, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Leenders
authors.forename: Wino J
authors.initials: WJ
authors.lastname: Wijnen
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Made
authors.forename: Monika
authors.initials: M
authors.lastname: Hiller
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Thierry
authors.initials: T
authors.lastname: Vandendriessche
authors.forename: Marinee
authors.initials: M
authors.lastname: Chuah
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099251:Myocardin
chemical_list: D000804:Angiotensin II; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D050505:Mutant Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C467418:Klf15 protein, mouse; C431575:MRTFA protein, human; C503315:myocardin-related transcription factor B, mouse