Physiological Genomics of Heart Failure: From Technology to Physiology
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Genome wide gene expression in cardiac disease is incompletely characterized. The main purpose of this project was to increase insight into molecular mechanisms of myocardial hypertrophy and heart failure in experimental models and human disease. We aimed to establish and use microarray technology and bioinformatics tools to obtain these results. Finally, we sought to relate gene/protein expression to function in vitro, by functional studies in isolated cardiac myocytes. Microarray technology and methods of data analysis were established which enabled detection of differentially expressed genes. Combining gene expression data and functional annotations yielded a biologically meaningful analysis which identified potentially important molecular mechanisms of end-stage heart disease and physiological hypertrophy. Gene expression classifiers were developed to distinguish between myocardial samples from end-stage heart failure, originating from either coronary artery disease or dilated cardiomypathy. Gene-class testing analysis indicated aetiology-specific patterns in coronary artery disease and dilated cardiomypathy, primarily related to genes involved in catabolism and regulation of protein kinase activity. Serial cardiac-specific gene expression was studied during the development of hypertrophy in congestive heart failure and exercise training. Our results suggest that one of the main molecular differences could be down-regulation of fatty acid metabolism genes, which was observed in pathological hypertrophy but not in exercise-induced hypertrophy. Congestive heart failure was associated with more comprehensive changes in gene expression than exercise training. This indicates that post-transcriptional and post-translational regulation may be important in physiological hypertrophy. All gene/protein annotations and gene-class analyses were generated by GeneTools, a program that was developed in our group during the project as an “all in one” annotation tool. In isolated rat ventricular cardiomyocytes, we showed that H+/K+-adenosine triphosphatase was expressed and regulated both at the transcript and protein level. Functional in vitro studies indicated that the H+/K+-ATPase may account for up to about 25% of the K+-uptake across the ventricular sarcolemma.
Has partsBeisvåg, Vidar; Falck, Geir; Loennechen, Jan P; Qvigstad, Gunnar; Jynge, Per; Skomedal, Tor; Osnes, Jan B.; Sandvik, Arne K.; Ellingsen, Øyvind. Identification and regulation of the gastric H+/K+-ATPase in the rat heart. Acta Physiologica Scandinavica. 179(3): 251-262, 2003.
Beisvåg, Vidar; Lehre, Per Kristian; Midelfart, Herman; Aass, Halfdan; Geiran, Odd; Sandvik, Arne K.; Lægreid, Astrid; Komorowski, Jan; Ellingsen, Øyvind. Aetiology-specific patterns in end-stage heart failure patients identified by functional annotation and classification of microarray data. European Journal of Heart Failure. 8(4): 381-389, 2006.
Beisvåg, Vidar; Jünge, Frode K. R.; Bergum, Hallgeir; Jølsum, Lars; Günther, Clara-Cecilie; Lydersen, Stian; Ramampiaro, Heri; Sandvik, Arne K.; Lægreid, Astrid. GeneTools – application for functional annotation and statistical hypothesis testing. BMC Bioinformatics. 7(1): 470, 2006.