title: Tapping the brake on cardiac growth-endogenous repressors of hypertrophic signaling.
abstract: Cardiac hypertrophy is considered an early hallmark during the clinical course of heart failure and an important risk factor for cardiac morbidity and mortality. Although hypertrophy of individual cardiomyocytes in response to pathological stimuli has traditionally been considered as an adaptive response required to sustain cardiac output, accumulating evidence from studies in patients and animal models suggests that in most instances hypertrophy of the heart also harbors maladaptive aspects. Major strides have been made in our understanding of the pathways that convey pro-hypertrophic signals from the outside of the cell to the nucleus. In recent years it also has become increasingly evident that the heart possesses a variety of endogenous feedback mechanisms to counterbalance this growth response. These repressive mechanisms are of particular interest since they may provide valuable therapeutic options. In this review we summarize currently known endogenous repressors of pathological cardiac growth as they have been studied by gene targeting in mice. Many of the repressors that function in signal transduction appear to regulate calcineurin (e.g. PICOT, calsarcin, RCAN) and JNK signaling (e.g. CDC42, MKP-1) and some will be described in greater detail in this review. In addition, we will focus on factors such as Kruppel-like factors (KLF4, KLF15 and KLF10) and histone deacetylases (HDACs), which constitute a relevant group of nuclear proteins that repress transcription of the hypertrophic gene program in cardiomyocytes.
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Leenders
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D012097:Repressor Proteins