Yu, Hongjuan

English

Heart failure (HF) is the common end stage syndrome of many cardiac disorders, including valve insufficiency (volume overload), hypertension (pressure overload), myocardial infarction and cardiomyopathies. These different initial events all result in altered ventricular wall stress triggering cardiac remodeling. One of the main processes that contributes to cardiac remodeling is cardiomyocyte growth (hypertrophy). Induction of hypertrophy is accompanied by marked changes in gene expression profiles of which the re-expression of fetal genes, the so called “fetal gene program” is well known1,2. The aim of this thesis was to generate an inventory of gene expression changes specific for cardiomyocyte hypertrophy and to further investigate the role of these changes in hypertrophy development (chapter 1). In particular, we explored the function of A kinase interacting protein 1 (AKIP1), which was identified in the inventory as a novel hypertrophy associated gene. That cardiomyocyte growth and changes in cardiomyocyte function are the underlying causes of cardiac hypertrophy and HF development has been recognized for ages. Unravelling the molecular mechanism underlying these processes has, however, only started in the last decades and it has become clear that these changes are very complex. In chapter 2, we reviewed the current knowledge on gene expression regulation during hypertrophy development. We described how neurohormonal and biomechanical signals are transduced to the nucleus and affect a set of transcription factors and chromatin modulators. Calcium signaling and protein (de)phosphorylation plays an essential role in this transduction process. Multiple transcription factors, including MEF2, GATA, Nkx-2.5 and NFAT, cooperate in controlling cardiomyocyte gene expression and binding sites for these proteins have been found in promoters of many hypertrophy associated genes. However, even for an extensively explored gene like ANP (atrial natriuretic protein) the regulation of its expression in vivo is still mysterious3. Genetic modulation of signal transduction pathways and transcription factors in in vitro studies and in animal models has shown that targeting these systems allows modulation of hypertrophy development. However, due to their central role, not only in cardiomyocytes, but also in many other cells it is unlikely that targeting these central systems will provide therapeutic opportunities. We therefore postulated that it might be more promising to investigate the potential downstream targets of these pathways. Several studies that target downstream genes are currently underway and provide promising results, like BNP4, SERCA5, and myosin6. Generating an inventory of hypertrophy associated genes may therefore allow the identification of new potential targets against HF

ARTS repository - University of Groningen

Exploring AKIP1 function in the heart

https://pure.rug.nl/ws/files/14500163/07_c7_summ_ackn_bio.pdf

Exploring AKIP1 function in the heart

Abstract

Similar works

Full text

Available Versions

ARTS repository - University of Groningen